Amlodipine valsartan side effects

Amlodipine / valsartan Side Effects

Medically reviewed by Drugs.com. Last updated on Feb 15, 2019.

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For the Consumer

Applies to amlodipine / valsartan: oral tablet

Warning

Oral route (Tablet)

If pregnancy is confirmed, discontinue amlodipine valsartan immediately. Injury and death to the developing fetus may result from drugs that act directly on the renin-angiotensin system

Along with its needed effects, amlodipine / valsartan may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking amlodipine / valsartan:

More common

  • Bloating or swelling of the face, arms, hands, lower legs, or feet
  • rapid weight gain
  • tingling of the hands or feet
  • unusual weight gain or loss

Less common

  • Body aches or pain
  • chills
  • cough
  • difficulty with breathing
  • dizziness
  • ear congestion
  • fever
  • headache
  • loss of voice
  • muscle aches
  • sneezing
  • sore throat
  • stuffy or runny nose
  • unusual tiredness or weakness

Rare

  • Ankle, knee, or great toe joint pain
  • bloody or cloudy urine
  • blurred or loss of vision
  • burning feeling in the chest or stomach
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
  • chest pain
  • cold sweats
  • confusion
  • congestion
  • cough producing mucus
  • diarrhea
  • difficult, burning, or painful urination
  • disturbed color perception
  • dizziness, faintness, or lightheadedness when getting up from a lying or sitting position
  • dry mouth
  • fast, irregular, pounding, or racing heartbeat or pulse
  • flushed, dry skin
  • heart murmur
  • hives
  • hoarseness
  • indigestion
  • itching
  • joint pain, stiffness, or swelling
  • loss of appetite
  • nausea
  • pain in the lower back, bottom, or hips
  • pain in the upper leg
  • pain or tenderness around the eyes and cheekbones
  • rash
  • redness of the skin
  • stomach cramps, tenderness, or pain
  • sweating
  • swelling of the eyelids, face, lips, hands, or feet
  • tightness of the chest
  • trouble with swallowing
  • troubled breathing
  • vomiting
  • watery or bloody diarrhea
  • weakness

Get emergency help immediately if any of the following symptoms of overdose occur while taking amlodipine / valsartan:

Symptoms of overdose

  • Chest discomfort
  • cold, clammy skin
  • fast, weak pulse
  • flushing
  • lightheadedness or fainting
  • slow heartbeat

Some side effects of amlodipine / valsartan may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Rare

  • Acid or sour stomach
  • back pain
  • belching
  • bone pain
  • continuing ringing or buzzing or other unexplained noise in the ears
  • difficulty having a bowel movement (stool)
  • difficulty with moving
  • fear or nervousness
  • feeling sad or empty
  • full or bloated feeling
  • hearing loss
  • heartburn
  • inability to have or keep an erection
  • increased sensitivity to sunlight
  • irritability
  • itching, pain, redness, or swelling of the eye or eyelid
  • lack or loss of strength
  • loss in sexual ability, desire, drive, or performance
  • loss of interest or pleasure
  • muscle aching or cramping
  • pain in the arms or legs
  • passing gas
  • pressure in the stomach
  • redness in the joints
  • redness of the skin
  • sensation of spinning
  • skin rash, encrusted, scaly, and oozing
  • sleepiness or unusual drowsiness
  • swelling of the abdominal or stomach area
  • tiredness
  • toothache
  • trouble concentrating
  • unable to sleep
  • unusually warm skin
  • watering of the eyes

For Healthcare Professionals

Applies to amlodipine / valsartan: oral tablet

General

The most common adverse reactions were BUN increased greater than 50%, peripheral edema, nasopharyngitis, upper respiratory tract infection, and dizziness.

Metabolic

Very common (10% or more): BUN increased greater than 50% (up to 10.9%)

Common (1% to 10%): Hypokalemia, serum potassium increased greater than 20%

Amlodipine:

Uncommon (0.1% to 1%): Weight increased, weight decreased

Very rare (less than 0.01%): Hyperglycemia

Common (1% to 10%): BUN increased

Frequency not reported: Serum potassium increased

Other

Common (1% to 10%): Asthenia, fatigue, facial edema, edema, peripheral edema, pitting edema

Uncommon (0.1% to 1%): Ear pain, chest pain, pyrexia

Amlodipine:

Very common (10% or more): Peripheral edema (up to 10.3%)

Common (1% to 10%): Fatigue, edema, ankle swelling

Uncommon (0.1% to 1%): Gynecomastia, asthenia, discomfort, malaise, non-cardiac chest pain, pain

Valsartan:

Common (1% to 10%): Peripheral edema

Uncommon (0.1% to 1%): Fatigue

Cardiovascular

Common (1% to 10%): Flushing, hot flush, orthostatic blood pressure decrease

Uncommon (0.1% to 1%): Palpitation, tachycardia, orthostatic hypotension

Rare (less than 0.1%): Hypotension

Amlodipine:

Common (1% to 10%): Palpitation, flushing

Uncommon (0.1% to 1%): Hypotension

Very rare (less than 0.01%): Arrhythmia, myocardial infarction, vasculitis

Valsartan:

Frequency not reported: Vasculitis

Respiratory

Common (1% to 10%): Nasopharyngitis, upper respiratory tract infection

Amlodipine:

Uncommon (0.1% to 1%): Dyspnea, rhinitis

Very rare (less than 0.01%): Cough

Valsartan:

Uncommon (0.1% to 1%): Cough

Nervous system

Common (1% to 10%): Headache, dizziness

Uncommon (0.1% to 1%): Coordination abnormal, dizziness postural, paresthesia, somnolence, vertigo, sciatica, cervicobrachial syndrome, carpal tunnel syndrome, hypoesthesia, sinus headache

Rare (less than 0.1%): Tinnitus, syncope

Amlodipine:

Common (1% to 10%): Dizziness, headache, somnolence

Uncommon (0.1% to 1%): Dysgeusia, paresthesia, syncope, tremor, hypoesthesia, tinnitus

Very rare (less than 0.01%): Hypertonia, peripheral neuropathy, neuropathy

Frequency not reported: Extrapyramidal syndrome

Valsartan:

Uncommon (0.1% to 1%): Vertigo

Musculoskeletal

Common (1% to 10%): Creatine kinase increased greater than 300%

Rare (less than 0.1%): Sensation of heaviness

Amlodipine:

Uncommon (0.1% to 1%): Arthralgia, back pain, muscle spasm, myalgia

Valsartan:

Frequency not reported: Myalgia

Postmarketing reports: Rhabdomyolysis

Immunologic

Common (1% to 10%): Influenza

Uncommon (0.1% to 1%): Seasonal allergy

Rare (less than 0.1%): Hypersensitivity

Amlodipine:

Very rare (less than 0.01%): Hypersensitivity

Valsartan:

Frequency not reported: Hypersensitivity

Renal

Common (1% to 10%): Creatinine increased greater than 50%

Uncommon (0.1% to 1%): Nephrolithiasis

Valsartan:

Frequency not reported: Serum creatinine increased, renal failure and impairment

Hepatic

Common (1% to 10%): ALT increased greater than 150%

Amlodipine:

Very rare (less than 0.01%): Liver function test abnormal, serum bilirubin increased, hepatitis, intrahepatic cholestasis, jaundice

Valsartan:

Frequency not reported: Liver function test abnormal, serum bilirubin increased

Gastrointestinal

Amlodipine:

Common (1% to 10%): Abdominal discomfort, upper abdominal pain, nausea

Uncommon (0.1% to 1%): Change of bowel habit, diarrhea, dry mouth, dyspepsia, vomiting

Very rare (less than 0.01%): Gastritis, gingival hyperplasia, pancreatitis

Valsartan:

Uncommon (0.1% to 1%): Abdominal discomfort, upper abdominal pain

Dermatologic

Uncommon (0.1% to 1%): Erythema, rash, pruritus, hyperhidrosis, eczema

Rare (less than 0.1%): Exanthema

Amlodipine:

Very rare (less than 0.01%): Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke edema

Valsartan:

Frequency not reported: Angioedema, dermatitis bullous, pruritus, rash

Genitourinary

Uncommon (0.1% to 1%): Hematuria, pollakiuria, erectile dysfunction

Rare (less than 0.1%): Polyuria

Amlodipine:

Uncommon (0.1% to 1%): Micturition disorder, nocturia, pollakiuria, impotence

Psychiatric

Uncommon (0.1% to 1%): Insomnia, anxiety, depression

Amlodipine:

Uncommon (0.1% to 1%): Depression, insomnia/sleep disorders, mood swings

Rare (less than 0.1%): Confusion

Ocular

Uncommon (0.1% to 1%): Visual impairment

Rare (less than 0.1%): Visual disturbance

Amlodipine:

Uncommon (0.1% to 1%): Visual disturbance, visual impairment

Hematologic

Uncommon (0.1% to 1%): Lymphadenopathy

Amlodipine:

Very rare (less than 0.01%): Leukopenia, thrombocytopenia

Valsartan:

Frequency not reported: Hemoglobin decreased, hematocrit decreased, neutropenia, thrombocytopenia

1. “Product Information. Exforge (amlodipine-valsartan).” Novartis Pharmaceuticals, East Hanover, NJ.

2. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0

3. Cerner Multum, Inc. “Australian Product Information.” O 0

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

Medical Disclaimer

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Exforge

CLINICAL PHARMACOLOGY

Mechanism Of Action

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 in vitro 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 AT1 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 AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th 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.

Pharmacodynamics

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 coadministered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular (AV) 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 (ECG) 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.

Sildenafil

When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect .

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 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.

Pharmacokinetics

Peak plasma concentrations of amlodipine are reached 6 to 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 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Following oral administration of valsartan alone peak plasma concentrations of valsartan are reached in 2 to 4 hours. Absolute bioavailability is about 25% (range 10% to 35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) 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 biexponential 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 coadministered 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).

Following oral administration of Exforge in normal healthy adults, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6 to 8 hours, respectively. The rate and extent of absorption of valsartan and amlodipine from Exforge are the same as when administered as individual tablets. The bioavailabilities of amlodipine and valsartan are not altered by the coadministration of food.

Special Populations

Geriatric

Amlodipine: Elderly patients have decreased clearance of amlodipine with a resulting increase in peak plasma levels, elimination half-life and AUC.

Valsartan: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary.

Gender

Valsartan: Pharmacokinetics of valsartan does not differ significantly between males and females.

Renal Insufficiency

Amlodipine: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment.

Valsartan: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance < 10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan.

Hepatic Insufficiency

Amlodipine: Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60%.

Valsartan: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease.

Drug Interactions

In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin and indomethacin.

Impact of Other Drugs on Amlodipine

Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

CYP3A inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent .

Impact of Amlodipine on Other Drugs

Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone .

Cyclosporine: A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine .

Tacrolimus: A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5-to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N= 6). However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs .

Developmental Toxicity Studies

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 MRHD of 10 mg amlodipine on a mg/m² 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/m² basis. (Calculations based on a patient weight of 60 kg.)

Amlodipine Besylate and Valsartan

In the oral embryofetal 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 embryofetal effects was 10 mg/kg/day amlodipine plus 160 mg/kg/day valsartan. On a systemic exposure basis, these doses are, respectively, 4.3, and 2.7 times the systemic exposure in humans receiving the MRHD (10/320 mg/60 kg).

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

Table 2: Effect of Exforge on Sitting Systolic Blood Pressure

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

Table 4: Effect of Exforge on Sitting Systolic Blood Pressure

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

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

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 to 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.

Generic Name: amlodipine and valsartan (am LOE de peen val SAR tan)
Brand Names: Exforge

Medically reviewed by Sophia Entringer, PharmD Last updated on Jun 20, 2019.

  • Overview
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What is Exforge?

Exforge contains a combination of amlodipine and valsartan. Amlodipine is a calcium channel blocker. It works by relaxing the muscles of your heart and blood vessels.

Valsartan is an angiotensin II receptor antagonist. Valsartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Exforge is used to treat high blood pressure (hypertension). Lowering blood pressure may lower your risk of a stroke or heart attack.

Exforge is usually given after other blood pressure medicines have been tried without success.

Important information

Do not use Exforge if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away.

If you have diabetes, do not use Exforge together with any medication that contains aliskiren (such as Amturnide, Tekturna, Valturna, or Tekamlo).

In rare cases, Exforge can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Do not use potassium supplements or salt substitutes while you are taking Exforge, unless your doctor has told you to.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Before taking this medicine

You should not use Exforge if you are allergic to amlodipine (Norvasc) or valsartan (Diovan).

If you have diabetes, do not use this medicine together with any medication that contains aliskiren (such as Amturnide, Tekturna, Valturna, or Tekamlo).

You may also need to avoid taking Exforge with aliskiren if you have kidney disease.

To make sure Exforge is safe for you, tell your doctor if you have ever had:

  • heart problems;

  • a heart attack;

  • kidney disease;

  • liver disease; or

  • if you are on a low-salt diet.

Do not use Exforge if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away. This medicine can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

It is not known whether amlodipine and valsartan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine before speaking with your doctor.

Exforge is not approved for use by anyone younger than 18 years old.

How should I take Exforge?

Take Exforge exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

You may take Exforge with or without food.

Your blood pressure will need to be checked often. Your kidney function may also need to be checked.

You may have very low blood pressure while taking Exforge. Call your doctor if you have a light-headed feeling or feel like you might pass out. Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual.

If you need surgery, tell the surgeon ahead of time that you are using Exforge.

It may take up to 4 weeks for this medication to control your blood pressure. Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Blood pressure medication is only part of a complete treatment program that may also include diet, exercise, regular blood pressure checks, lifestyle changes, and other medications. Follow your doctor’s instructions very carefully.

Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or stop taking any of your medications without your doctor’s advice.

Store at room temperature away from moisture and heat.

Exforge dosing information

Usual Adult Dose for Hypertension:

Initial therapy: Amlodipine 5 mg-Valsartan 160 mg orally once a day
Add-on/Replacement therapy: Amlodipine 5 to 10 mg-Valsartan 160 to 320 mg orally once a day

-May increase dose after 1 to 2 weeks of therapy.
-A patient who experiences dose-limiting adverse reactions from either drug component alone may be switched to Exforge which contains a lower dose of each drug component in combination with the other. If blood pressure remains uncontrolled after 3 to 4 weeks, may titrate up to a maximum of amlodipine 10 mg-valsartan 320 mg orally once a day.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Exforge?

Do not use potassium supplements or salt substitutes while you are taking Exforge, unless your doctor has told you to.

Drinking alcohol can further lower your blood pressure and may cause side effects.

Exforge may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Exforge side effects

Get emergency medical help if you have signs of an allergic reaction to Exforge: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • a light-headed feeling, like you might pass out;

  • swelling in your hands or feet, rapid weight gain; or

  • signs of an electrolyte imbalance – dry mouth, increased thirst, drowsiness, confusion, feeling restless, vomiting, muscle pain or weakness, lack of energy, fast heartbeats, little or no urine, or a seizure.

Common Exforge side effects include:

  • swelling in your hands or feet;

  • headache and dizziness; or

  • cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Exforge?

Many drugs can interact with amlodipine and valsartan. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

  • all your heart or blood pressure medicines;

  • cyclosporine;

  • lithium;

  • ritonavir;

  • a diuretic or “water pill”;

  • vitamin or mineral supplements that contain potassium;

  • simvastatin or other cholesterol medication;

  • an antibiotic – clarithromycin, rifabutin, rifampin, rifapentine, telithromycin;

  • antifungal medicine – itraconazole, ketoconazole; or

  • NSAIDs (nonsteroidal anti-inflammatory drugs) – aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete and many other drugs can interact with amlodipine and valsartan. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2020 Cerner Multum, Inc. Version: 9.01.

Medical Disclaimer

More about Exforge (amlodipine / valsartan)

  • Side Effects
  • During Pregnancy
  • Dosage Information
  • Drug Images
  • Drug Interactions
  • Support Group
  • Pricing & Coupons
  • En Español
  • 54 Reviews
  • Generic Availability
  • Drug class: angiotensin II inhibitors with calcium channel blockers
  • FDA Alerts (7)
  • FDA Approval History
  • Exforge
  • Exforge (Advanced Reading)
  • Exforge (FDA)

Other Formulations

  • Exforge HCT
  • High Blood Pressure

Exforge HCT

SIDE EFFECTS

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

In the controlled trial of Exforge HCT, where only the maximum dose (10/320/25 mg) was evaluated, safety data were obtained in 582 patients with hypertension. 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 similar between men and women, younger ( < 65 years) and older ( > 65 years) patients, and black and white patients. In the active controlled clinical trial, discontinuation because of adverse events occurred in 4.0% of patients treated with Exforge HCT 10/320/25 mg compared to 2.9% of patients treated with valsartan/HCTZ 320/25 mg, 1.6% of patients treated with amlodipine/valsartan 10/320 mg, and 3.4% of patients treated with HCTZ/amlodipine 25/10 mg. The most common reasons for discontinuation of therapy with Exforge HCT were dizziness (1.0%) and hypotension (0.7%).

The most frequent adverse events that occurred in the active controlled clinical trial in at least 2% of patients treated with Exforge HCT are presented in the following table.

Orthostatic events (orthostatic hypotension and postural dizziness) were seen in 0.5% of patients. Other adverse reactions that occurred in clinical trials with Exforge HCT ( > 0.2%) are listed below. It cannot be determined whether these events were causally related to Exforge HCT.

Cardiac Disorders: tachycardia

Ear and Labyrinth Disorders: vertigo, tinnitus

Eye Disorders: vision blurred

Gastrointestinal Disorders: diarrhea, abdominal pain upper, vomiting, abdominal pain, toothache, dry mouth, gastritis, hemorrhoids

General Disorders and Administration Site Conditions: asthenia, noncardiac chest pain, chills, malaise

Infections and Infestations: upper respiratory tract infection, bronchitis, influenza, pharyngitis, tooth abscess, gastroenteritis viral, respiratory tract infection, rhinitis, urinary tract infection

Injury, Poisoning and Procedural Complications: back injury, contusion, joint sprain, procedural pain

Investigations: blood uric acid increased, blood creatine phosphokinase increased, weight decreased

Metabolism and Nutrition Disorders: hypokalemia, diabetes mellitus, hyperlipidemia, hyponatremia

Musculoskeletal and Connective Tissue Disorders: pain in extremity, arthralgia, musculoskeletal pain, muscular weakness, musculoskeletal weakness, musculoskeletal stiffness, joint swelling, neck pain, osteoarthritis, tendonitis

Nervous System Disorders: paresthesia, somnolence, syncope, carpal tunnel syndrome, disturbance in attention, dizziness postural, dysgeusia, head discomfort, lethargy, sinus headache, tremor

Psychiatric Disorders: anxiety, depression, insomnia

Renal and Urinary Disorders: pollakiuria

Reproductive System and Breast Disorders: erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders: dyspnea, nasal congestion, cough, pharyngolaryngeal pain

Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis, night sweats, rash

Vascular Disorders: hypotension

Isolated cases of the following clinically notable adverse reactions were also observed in clinical trials: anorexia, constipation, dehydration, dysuria, increased appetite, viral infection.

Amlodipine has been evaluated for safety in more than 11000 patients in US and foreign clinical trials. Other adverse reactions not listed above that have been reported in < 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were:

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, postural hypotension, vasculitis

Central and Peripheral Nervous System: neuropathy peripheral, tremor

Gastrointestinal: anorexia, dysphagia, pancreatitis, gingival hyperplasia

General: allergic reaction, hot flushes, malaise, rigors, weight gain

Musculoskeletal System: arthrosis, muscle cramps

Psychiatric: sexual dysfunction (male and female), nervousness, abnormal dreams, depersonalization

Skin and Appendages: angioedema, erythema multiforme, rash erythematous, rash maculopapular

Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus

Urinary System: micturition frequency, micturition disorder, nocturia

Autonomic Nervous System: sweating increased

Metabolic and Nutritional: hyperglycemia, thirst

Hemopoietic: leukopenia, purpura, thrombocytopenia

Other adverse reactions 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 its full prescribing information.

Valsartan has been evaluated for safety in more than 4000 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 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 < 0.001).

Other adverse reactions, not listed above, occurring in > 0.2% of patients in controlled clinical trials with valsartan are:

Digestive: flatulence

Respiratory: sinusitis, pharyngitis

Urogenital: impotence

Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan.

Hydrochlorothiazide

Other adverse reactions not listed above that have been reported with hydrochlorothiazide, without regard to causality, are listed below:

Body as a Whole: weakness

Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation

Hematologic: aplastic anemia, agranulocytosis, hemolytic anemia

Hypersensitivity: photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions

Metabolic: glycosuria, hyperuricemia

Nervous System/Psychiatric: restlessness

Renal: renal failure, renal dysfunction, interstitial nephritis

Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis

Special Senses: transient blurred vision, xanthopsia.

Clinical Laboratory Test Findings

Clinical laboratory test findings for Exforge HCT were obtained in a controlled trial of Exforge HCT administered at the maximal dose of 10/320/25 mg compared to maximal doses of dual therapies, i.e., valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, and HCTZ/amlodipine 25/10 mg. Findings for the components of Exforge HCT were obtained from other trials.

Creatinine: In hypertensive patients, greater than 50% increases in creatinine occurred in 2.1% of Exforge HCT patients compared to 2.4% of valsartan/HCTZ patients, 0.7% of amlodipine/valsartan patients, and 1.8% of HCTZ/amlodipine patients.

In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.

Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Exforge HCT-treated patients.

Blood Urea Nitrogen (BUN): In hypertensive patients, greater than 50% increases in BUN were observed in 30% of Exforge HCT-treated patients compared to 29% of valsartan/HCTZ patients, 15.8% of amlodipine/valsartan patients, and 18.5% of HCTZ/amlodipine patients. The majority of BUN values remained within normal limits.

In heart failure patients, greater than 50% increases in BUN were observed in 17% of valsartan-treated patients compared to 6% of placebo-treated patients.

Serum Electrolytes (Potassium): In hypertensive patients, greater than 20% decreases in serum potassium were observed in 6.5% of Exforge HCT-treated patients compared to 3.3% of valsartan/HCTZ patients, 0.4% of amlodipine/valsartan patients, and 19.3% of HCTZ/amlodipine patients. Greater than 20% increases in potassium were observed in 3.5% of Exforge HCT-treated patients compared to 2.4% of valsartan/HCTZ patients, 6.2% of amlodipine/valsartan patients, and 2.2% of HCTZ/amlodipine patients.

In heart failure patients, greater than 20% increases in serum potassium were observed in 10% of valsartantreated patients compared to 5.1% of placebo-treated patients .

Neutropenia: Neutropenia ( < 1500/L) was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo.

Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

With amlodipine, gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

The following additional adverse reactions have been reported in postmarketing experience with valsartan or valsartan/hydrochlorothiazide:

Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, neutropenia Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Exforge HCT should not be re-administered to patients who have had angioedema.

Digestive: Elevated liver enzymes and very rare reports of hepatitis

Renal: Impaired renal function, renal failure

Clinical Laboratory Tests: Hyperkalemia

Dermatologic: Alopecia, bullous dermatitis

Vascular: Vasculitis

Nervous System: Syncope

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

The following additional adverse reactions have been reported in postmarketing experience with hydrochlorothiazide:

Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, visual impairment.

Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary.

Read the entire FDA prescribing information for Exforge HCT (Amlodipine Valsartan Hydrochlorothiazide Tablets)

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