Exforge HCT

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

WARNING: FETAL TOXICITY

• When pregnancy is detected, discontinue Exforge HCT as soon as possible. (5.1)


• Drugs that act directly on the renin-angiotensin system can cause injury or death to the developing fetus. (5.1)

Indications and Usage for Exforge HCT

Exforge HCT (amlodipine, valsartan, hydrochlorothiazide) is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including amlodipine, hydrochlorothiazide and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with Exforge HCT.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

This fixed combination drug is not indicated for the initial therapy of hypertension [see Dosage and Administration (2)].

Exforge HCT Dosage and Administration

General Considerations

Dose once-daily. The dosage may be increased after two weeks of therapy. The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose of Exforge HCT. The maximum recommended dose of Exforge HCT is 10/320/25 mg.

Exforge HCT may be administered with or without food.

No initial dosage adjustment is required for elderly patients.

Renal impairment: The usual regimens of therapy with Exforge HCT may be followed if the patient’s creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so avoid use of Exforge HCT [see Impaired Renal Function (5.5)].

Hepatic impairment: Avoid Exforge HCT in patients with severe hepatic impairment. In patients with lesser degrees of hepatic impairment, monitor for worsening of hepatic or renal function and adverse reactions [see Impaired Hepatic Function (5.4)].

Add-on / Switch Therapy

Exforge HCT may be used for patients not adequately controlled on any two of the following antihypertensive classes: calcium channel blockers, angiotensin receptor blockers, and diuretics.

A patient who experiences dose-limiting adverse reactions to an individual component while on any dual combination of the components of Exforge HCT may be switched to Exforge HCT containing a lower dose of that component to achieve similar blood pressure reductions.

Replacement Therapy

Exforge HCT may be substituted for the individually titrated components.

Dosage Forms and Strengths

• 5 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets – White, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VCL” on the other side.
  


• 10 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets – Pale yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VDL” on the other side.
  


• 5 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets – Yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VEL” on the other side.
  


• 10 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets – Brown-yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VHL” on the other side.
  


• 10 mg amlodipine /320 mg valsartan /25 mg hydrochlorothiazide Tablets – Brown-yellow, non-scored, film-coated tablet, ovaloid, biconvex with beveled edge with debossing “NVR” on one side and “VFL” on the other side.

Contraindications

Because of the hydrochlorothiazide component, Exforge HCT is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Warnings and Precautions

Fetal Toxicity

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 HCT as soon as possible [see Use in Specific Populations (8.1)].

Hypotension in Volume- or Salt-Depleted Patients 

Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with the maximum dose of Exforge HCT (10/320/25 mg) compared to 1.8% of valsartan/HCTZ (320/25 mg) patients, 0.4% of amlodipine/valsartan (10/320 mg) patients, and 0.2% of HCTZ/amlodipine (25/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension. In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Correct this condition prior to administration of Exforge HCT.

Exforge HCT has not been studied in patients with heart failure, recent myocardial infarction, or 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. Do not initiate treatment with Exforge HCT in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

If excessive hypotension occurs with Exforge HCT, 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.

Increased Angina and/or Myocardial Infarction

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

Impaired Hepatic Function

Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with impaired hepatic function.

As the majority of valsartan is eliminated in the bile, patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance (higher AUCs).

In patients with impaired hepatic function or progressive liver disease, minor alterations of fluid and electrolyte balance, such as those resulting from diuretic use, may precipitate hepatic coma.

Therefore, avoid the use of Exforge HCT in patients with severe hepatic impairment. When administering Exforge HCT to patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, monitor for worsening of hepatic or renal function, including fluid status and electrolytes, and adverse reactions.

Impaired Renal Function 

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. 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.

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.

In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Avoid use of Exforge HCT in severe renal disease (creatinine clearance ≤30 mL/min). The usual regimens of therapy with Exforge HCT may be followed if the patient’s creatinine clearance is >30 mL/min.

There is no experience in the use of Exforge HCT in patients with a recent kidney transplant.

Heart Failure

Exforge HCT has not been studied in patients with heart failure.

Studies with amlodipine: In general, calcium channel blockers should be used with close monitoring, including close follow-up of fluid status, electrolytes, renal function, and blood pressure in patients with heart failure. Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1,153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.

Studies with valsartan: Some patients with heart failure have developed increases in blood urea nitrogen, serum creatinine, and potassium on valsartan. 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 the diuretic and/or valsartan may be required. In the Valsartan Heart Failure Trial, in which 93% of patients were on concomitant ACE inhibitors, treatment was discontinued for elevations in creatinine or potassium (total of 1.0% on valsartan vs. 0.2% on placebo). In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), discontinuation due to various types of renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.

Hypersensitivity Reaction

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Lithium Interaction

Lithium generally should not be given with thiazides [see Drug Interactions, Hydrochlorothiazide, Lithium (7)].

Electrolytes and Metabolic Imbalances

Amlodipine -Valsartan - Hydrochlorothiazide

In the controlled trial of Exforge HCT in moderate to severe hypertensive patients, the incidence of hypokalemia (serum potassium <3.5 mEq/L) at any time post-baseline with the maximum dose of Exforge HCT (10/320/25 mg) was 10% compared to 25% with HCTZ/amlodipine (25/10 mg), 7% with valsartan/HCTZ (320/25 mg), and 3% with amlodipine/valsartan (10/320 mg). One patient (0.2%) discontinued therapy due to an adverse event of hypokalemia in each of the Exforge HCT and HCTZ/amlodipine groups. The incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% with Exforge HCT compared to 0.2-0.7% with the dual therapies. Monitor serum electrolytes periodically based on Exforge HCT use and other factors such as renal function, other medications, or history of prior electrolyte imbalances.

Hydrochlorothiazide 

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident, consider withholding or discontinuing Exforge HCT therapy or substituting other antihypertensive therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Exforge HCT should be discontinued or non-thiazide antihypertensive therapy substituted before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Adverse Reactions

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 table below:

Preferred Term	Aml/Val/HCTZ 10/320/25 mg N=582 n (%)	Val/HCTZ 320/25 mg N=559 n (%)	Aml/Val 10/320 mg N=566 n (%)	HCTZ/Aml 25/10 mg N=561 n (%)
Dizziness	48 (8.2)	40 (7.2)	14 (2.5)	23 (4.1)
Edema	38 (6.5)	8 (1.4)	65 (11.5)	63 (11.2)
Headache	30 (5.2)	31 (5.5)	30 (5.3)	40 (7.1)
Dyspepsia	13 (2.2)	5 (0.9)	6 (1.1)	2 (0.4)
Fatigue	13 (2.2)	15 (2.7)	12 (2.1)	8 (1.4)
Muscle spasms	13 (2.2)	7 (1.3)	7 (1.2)	5 (0.9)
Back pain	12 (2.1)	13 (2.3)	5 (0.9)	12 (2.1)
Nausea	12 (2.1)	7 (1.3)	10 (1.8)	12 (2.1)
Nasopharyngitis	12 (2.1)	13 (2.3)	13 (2.3)	12 (2.1)

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, non-cardiac 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: hypokalaemia, 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

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. 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  

Valsartan 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 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.

Post-Marketing Experience

Amlodipine

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.

Valsartan

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

Blood and Lymphatic: There are very rare reports of thrombocytopenia.

Hypersensitivity: There are rare reports of angioedema.

Digestive: Elevated liver enzymes and very rare reports of hepatitis

Renal: Impaired renal function

Clinical Laboratory Tests: Hyperkalemia

Dermatologic: Alopecia

Vascular: Vasculitis

Nervous System: Syncope

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

Drug Interactions

No drug interaction studies have been conducted with Exforge HCT and other drugs, although studies have been conducted with the individual components. A pharmacokinetic drug-drug interaction study has been conducted to address the potential for pharmacokinetic interaction between the triple combination, Exforge HCT, and the corresponding three double combinations. No clinically relevant interaction was observed.

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: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.

Magnesium and aluminum hydroxide (antacid): Co-administration of the magnesium and aluminum hydroxide antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.

Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Warfarin: Co-administration of amlodipine with warfarin did not change 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. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

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.

In vitro metabolism studies have indicated that CYP450 mediated drug interaction between valsartan and co-administered drugs are unlikely because of the low extent of metabolism [see Pharmacokinetics – Valsartan, (12.3)].

Co-administration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.

As with other drugs that block angiotensin II or its effects, concomitant use of 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.

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, co-administration 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.

Hydrochlorothiazide

When administered concurrently the following drugs may interact with thiazide diuretics:

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs: Additive effect or potentiation.

Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43% respectively.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.

Lithium: Should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Exforge HCT.

Non-steroidal anti-inflammatory drugs: In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics.

Carbamazepine: May lead to symptomatic hyponatremia.

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 valsartan-treated patients compared to 5.1% of placebo-treated patients [see Warnings and Precautions, Electrolytes and Metabolic Imbalances (5.10)].

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

Drug/Food Interactions

The bioavailability of amlodipine, valsartan, and HCTZ were not altered when Exforge HCT was administered with food.

USE IN SPECIFIC POPULATIONS 

Pregnancy

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 HCT as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Exforge HCT, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Exforge HCT for hypotension, oliguria, and hyperkalemia. [see Use in Specific Populations (8.4)]

Nursing Mothers

It is not known whether amlodipine and valsartan are excreted in human milk, but thiazides are excreted in human milk and valsartan is excreted in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Exforge HCT in pediatric patients have not been established.

Neonates with a history of in utero exposure to Exforge HCT:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Geriatric Use

In controlled clinical trials, 82 hypertensive patients treated with Exforge HCT were ≥65 years and 13 were ≥75 years. No overall differences in the efficacy or safety of Exforge HCT were observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.

Overdosage

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

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/m2 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 were noted.

If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Valsartan

Depressed level of consciousness, circulatory collapse and shock have been reported.

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 31 times, respectively, the maximum recommended human dose on a mg/m2 basis). (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

Hydrochlorothiazide

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The most common signs and symptoms observed in patients are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, 2000 and 4000 times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)

Valsartan and Hydrochlorothiazide

In rats and marmosets, single oral doses of valsartan up to 1524 and 762 mg/kg in combination with hydrochlorothiazide at doses up to 476 and 238 mg/kg, respectively, were very well tolerated without any treatment-related effects. These no adverse effect doses in rats and marmosets, respectively, represent 46.5 and 23 times the maximum recommended human dose (MRHD) of valsartan and 188 and 113 times the MRHD of hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)

Exforge HCT Description

Exforge HCT is a fixed combination of amlodipine, valsartan and hydrochlorothiazide.

Exforge HCT contains the besylate salt of amlodipine, a dihydropyridine calcium channel blocker (CCB). Amlodipine besylate, USP 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 (±) - 2 - [(2 - aminoethoxy)methyl] - 4 - (o - chlorophenyl) - 1,4 - dihydro - 6 - methyl - 3,5 - pyridinedicarboxylate, monobenzenesulfonate ; its structural formula is

Its empirical formula is C20H25ClN2O5•C6H6O3S and its molecular weight is 567.1.

Valsartan, USP is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT1 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 C24H29N5O3 and its molecular weight is 435.5.

Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide 1,1-dioxide.

Hydrochlorothiazide is a thiazide diuretic. Its empirical formula is C7H8ClN3O4S2, its molecular weight is 297.73, and its structural formula is

Exforge HCT film-coated tablets are formulated in five strengths for oral administration with a combination of amlodipine besylate, valsartan and hydrochlorothiazide, providing for the following available combinations: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg and 10/320/25 mg amlodipine besylate/valsartan/hydrochlorothiazide. The inactive ingredients for all strengths of the tablets include microcrystalline cellulose; crospovidone; colloidal anhydrous silica; magnesium stearate; hypromellose, macrogol 4000 and talc. Additionally, the 5/160/12.5 mg strength contains titanium dioxide; the 10/160/12.5 mg strength contains titanium dioxide and yellow and red iron oxides; the 5/160/25 mg strength contains titanium dioxide and yellow iron oxide and the 10/160/25 mg and 10/320/25 mg strengths