Amlodipine and Valsartan: Package Insert and Label Information

AMLODIPINE AND VALSARTAN — amlodipine besylate and valsartan tablet
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

1.1 Hypertension

Amlodipine and valsartan tablets are 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 and the angiotensin II receptor blocker (ARB) class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with amlodipine and valsartan tablets.

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 1 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. Amlodipine and valsartan tablets are indicated for the treatment of hypertension.

Amlodipine and valsartan tablets may be used in patients whose blood pressure is not adequately controlled on either monotherapy.

Amlodipine and valsartan tablets may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.

The choice of amlodipine and valsartan tablets as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the lowest dose of amlodipine and valsartan tablets.

Patients with stage 2 hypertension (moderate or severe) are at a relatively higher risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk.

Data from the high-dose multifactorial study [see Clinical Studies (14)] provide estimates of the probability of reaching a blood pressure goal with amlodipine and valsartan tablets compared to amlodipine or valsartan monotherapy. The figures below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with amlodipine and valsartan tablets 10/320 mg, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures.

Figure 1: Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8

Figure 2: Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8

Figure 3: Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8

Figure 4: Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8

For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 67% likelihood of achieving a goal of <140 mmHg (systolic) and 80% likelihood of achieving <90 mmHg (diastolic) on amlodipine alone, and the likelihood of achieving these goals on valsartan alone is about 47% (systolic) or 62% (diastolic). The likelihood of achieving these goals on amlodipine and valsartan tablets rises to about 80% (systolic) or 85% (diastolic). The likelihood of achieving these goals on placebo is about 28% (systolic) or 37% (diastolic).

2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

Dose once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 10/320 mg tablet once daily as needed to control blood pressure. The majority of the antihypertensive effect is attained within 2 weeks after initiation of therapy or a change in dose.

Amlodipine and valsartan tablets may be administered with other antihypertensive agents.

2.2 Add-on Therapy

A patient whose blood pressure is not adequately controlled with amlodipine (or another dihydropyridine calcium-channel blocker) alone or with valsartan (or another ARB) alone may be switched to combination therapy with amlodipine and valsartan tablets.

A patient who experiences dose-limiting adverse reactions on either component alone may be switched to amlodipine and valsartan tablets containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. The clinical response to amlodipine and valsartan tablets should be subsequently evaluated and if blood pressure remains uncontrolled after 3 to 4 weeks of therapy, the dose may be titrated up to a maximum of

10/320 mg.

2.3 Replacement Therapy

For convenience, patients receiving amlodipine and valsartan from separate tablets may instead wish to receive tablets of amlodipine and valsartan tablets containing the same component doses.

2.4 Initial Therapy

A patient may be initiated on amlodipine and valsartan tablets if it is unlikely that control of blood pressure would be achieved with a single agent. The usual starting dose is amlodipine and valsartan tablets 5/160 mg once daily in patients who are not volume-depleted.

3 DOSAGE FORMS AND STRENGTHS

(Amlodipine and valsartan) tablets are available as follows:

5/160 mg tablets, debossed with LU/Q12 (side 1/side 2)

10/160 mg tablets, debossed with LU/Q14

5/320 mg tablets, debossed with LU/Q13

10/320 mg tablets, debossed with LU/Q15

4 CONTRAINDICATIONS

Do not use in patients with known hypersensitivity to any component.

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

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

Amlodipine and valsartan tablets can cause fetal harm when administered to a pregnant woman. 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 and valsartan tablets as soon as possible [see Use in Specific Populations (8.1)].

5.2 Hypotension

Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with amlodipine and valsartan tablets in placebo-controlled studies. In patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Volume depletion should be corrected prior to administration of amlodipine and valsartan tablets. Treatment with amlodipine and valsartan tablets should start under close medical supervision.

Initiate therapy cautiously in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.

Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should be exercised when administering amlodipine, particularly in patients with severe aortic stenosis.

If excessive hypotension occurs with amlodipine and valsartan tablets, place the patient in a supine position and, if necessary, give intravenous 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.

5.3 Risk of Myocardial Infarction or Increased Angina

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

5.4 Impaired Renal Function

Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on amlodipine and valsartan tablets. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on amlodipine and valsartan tablets [see Drug Interactions (7)].

5.5 Hyperkalemia

Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.

Some patients with heart failure have developed increases in potassium with valsartan therapy. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of amlodipine and valsartan tablets may be required. [see Adverse Reactions (6.1)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Studies with Amlodipine and Valsartan Tablets

Amlodipine and valsartan tablets has been evaluated for safety in over 2600 patients with hypertension; over 1440 of these patients were treated for at least 6 months and over 540 of these patients were treated for at least 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.

The hazards [see Warnings and Precautions (5)] of valsartan are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter.

The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the amlodipine and valsartan tablets-treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with amlodipine and valsartan tablets were peripheral edema (0.4%), and vertigo (0.2%).

The adverse reactions that occurred in placebo-controlled clinical trials in at least 2% of patients treated with amlodipine and valsartan tablets but at a higher incidence in amlodipine/valsartan patients (n=1437) than placebo (n=337) included peripheral edema (5.4% vs. 3.0%), nasopharyngitis (4.3% vs 1.8%), upper respiratory tract infection (2.9% vs 2.1%) and dizziness (2.1% vs 0.9%).

Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients.

Studies with Valsartan

Diovan^®# has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. In trials in which valsartan was compared to an angiotensin-converting enzyme (ACE) inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p<0.001).

Clinical Lab Test Findings

Creatinine:

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.

Blood Urea Nitrogen (BUN):

In hypertensive patients, greater than 50% increases in BUN were observed in 5.5% of amlodipine and valsartan tablets-treated patients compared to 4.7% of placebo-treated patients. In heart failure patients, greater than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-treated patients. [see Warnings and Precautions (5.4)].

Neutropenia:

Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo.