AMLODIPINE, VALSARTAN, HYDROCHLOROTHIAZIDE

AMLODIPINE, VALSARTAN, HYDROCHLOROTHIAZIDE- amlodipine besylate, valsartan and hydrochlorothiazide tablet, film coated
AMLODIPINE, VALSARTAN, HYDROCHLOROTHIAZIDE- amlodipine besylate, hydrochlorothiazide and valsartan tablet, film coated
Par Pharmaceutical, Inc.

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning

When pregnancy is detected, discontinue amlodipine/valsartan/hydrochlorothiazide as soon as possible (5.1)

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

1 INDICATIONS AND USAGE

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 amlodipine/valsartan/hydrochlorothiazide.

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 (e.g., 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)].

2 DOSAGE AND ADMINISTRATION

2.1 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 amlodipine/valsartan/hydrochlorothiazide. The maximum recommended dose of amlodipine/valsartan/hydrochlorothiazide is 10/320/25 mg.

2.2 Add-on / Switch Therapy

Amlodipine/valsartan/hydrochlorothiazide 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 amlodipine/valsartan/hydrochlorothiazide may be switched to amlodipine/valsartan/hydrochlorothiazide containing a lower dose of that component to achieve similar blood pressure reductions.

2.3 Replacement Therapy

Amlodipine/valsartan/hydrochlorothiazide may be substituted for the individually titrated components.

2.4 Use with Other Antihypertensive Drugs

Amlodipine/valsartan/hydrochlorothiazide may be administered with other antihypertensive agents.

3 DOSAGE FORMS AND STRENGTHS

  • 5 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide tablets – White to off-white, film coated, oval shaped biconvex tablets, debossed with “P” on one side of the tablet and “172″ on the other.
  • 10 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide tablets – Peach to light brown, film coated, oval shaped biconvex tablets, debossed with “P” on one side of the tablet and “174″ on the other.
  • 5 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide tablets – Yellow, film-coated, oval shaped biconvex tablets debossed with “P” on one side of the tablet and “173” on the other.
  • 10 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide tablets – Bright yellow, film-coated oval shaped, biconvex tablets debossed with “P” on one side of the tablet and “185” on the other.
  • 10 mg amlodipine /320 mg valsartan /25 mg hydrochlorothiazide tablets – White to off-white, film coated, oval shaped biconvex tablets, debossed with “P” on one side of the tablet and “175″ on the other.

4 CONTRAINDICATIONS

Do not use in patients with anuria, hypersensitivity to other sulfonamide-derived drugs, or hypersensitivity to any component of this product.

Do not coadminister aliskiren with amlodipine/valsartan/hydrochlorothiazide in patients with diabetes [see Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1 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 amlodipine/valsartan/hydrochlorothiazide as soon as possible [see Use in Specific Populations (8.1)].

5.2 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 amlodipine/valsartan/hydrochlorothiazide (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 amlodipine/valsartan/hydrochlorothiazide.

Amlodipine/valsartan/hydrochlorothiazide 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 amlodipine/valsartan/hydrochlorothiazide in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

If excessive hypotension occurs with amlodipine/valsartan/hydrochlorothiazide, 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.

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