Amlodipine and Valsartan (Page 2 of 8)

3 DOSAGE FORMS AND STRENGTHS

5 mg/160 mg tablets are yellow colored, ovaloid shaped, beveled edge, biconvex film-coated tablets, debossed with ‘L’ on one side and ‘35’ on other side.
10 mg/160 mg tablets are light yellow colored, ovaloid shaped, beveled edge, biconvex film-coated tablets, debossed with ‘L’ on one side and ‘36’ on other side.
5 mg/320 mg tablets are very dark yellow colored, ovaloid shaped, beveled edge, biconvex film-coated tablets, debossed with ‘L’ on one side and ‘37’ on other side.
10 mg/320 mg tablets are yellow colored, ovaloid shaped, beveled edge, biconvex film-coated tablets, debossed with ‘L’ on one side and ‘38’ on other side.

4 CONTRAINDICATIONS

Do not use in patients with known hypersensitivity to any component.
Do not coadminister aliskiren with amlodipine and valsartan tablets in patients with diabetes [see Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

Amlodipine and valsartan 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 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 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. Treatment with amlodipine and valsartan 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, 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. 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 [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 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:

Amlodipine and valsartan 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-treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with amlodipine and valsartan 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 but at a higher incidence in amlodipine/valsartan patients (n=1437) than placebo (n=337) included peripheral edema (5.4% vs. 3%), 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:

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 had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, hydrochlorothiazide, 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-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 valsartan and 0.8% of patients treated with placebo.

6.2 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.

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 postmarketing experience with valsartan:

Hypersensitivity: Angioedema has been reported. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan should not be re-administered to patients who have had angioedema.

Digestive: Elevated liver enzymes and reports of hepatitis

Musculoskeletal: Rhabdomyolysis

Renal: Impaired renal function, renal failure

Dermatologic: Alopecia, bullous dermatitis

Blood and Lymphatic: Thrombocytopenia

Vascular: Vasculitis

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