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ADDITIONAL IMPORTANT SAFETY INFORMATION FOR DIOVAN, DIOVAN HCT, EXFORGE, EXFORGE HCT:

ADDITIONAL IMPORTANT SAFETY INFORMATION FOR TEKTURNA, TEKTURNA HCT, TEKAMLO, AND VALTURNA:

DIOVAN HCT and EXFORGE HCT are contraindicated in patients who are hypersensitive to any product components and in patients with anuria or hypersensitivity to sulfonamide-derived drugs.

Hypotension: Excessive hypotension was seen in patients treated with DIOVAN, DIOVAN HCT, EXFORGE, or EXFORGE HCT. Volume- and/or salt-depletion should be corrected in patients before administering DIOVAN, DIOVAN HCT, EXFORGE, or EXFORGE HCT or symptomatic hypotension may occur. Caution should be observed when initiating DIOVAN or EXFORGE in patients with heart failure or recent myocardial infarction, and in patients undergoing surgery or dialysis. Do not initiate treatment with EXFORGE HCT in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Risk of MI or Angina: EXFORGE and EXFORGE HCT contain the calcium channel blocker amlodipine. Rarely, increased frequency, duration, and/or severity of angina or acute myocardial infarction have developed in patients treated with calcium channel blockers, particularly those with severe obstructive coronary artery disease.

Hepatic Considerations: EXFORGE should be used with caution in patients with severe hepatic impairment. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t-1/2) is 56 hours in these patients. Avoid use of EXFORGE HCT in patients with severe hepatic impairment.

DIOVAN, DIOVAN HCT, EXFORGE, and EXFORGE HCT should be used with caution in patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, because of lower valsartan clearance. Monitor these patients for worsening of hepatic or renal function, including fluid status and electrolytes.

Renal Considerations: 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 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 (increases in serum creatinine or blood urea nitrogen) should be anticipated with DIOVAN, DIOVAN HCT, EXFORGE, and EXFORGE HCT.

Caution should be exercised when dosing DIOVAN, DIOVAN HCT, EXFORGE and EXFORGE HCT in patients with renal artery stenosis or severe heart failure. As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be observed. In patients with severe heart failure, decline in renal function and, rarely, acute renal failure and/or death has been associated with inhibiting the renin-angiotensin system.

Patients With CHF or Post-MI: Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function. Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required.

Hyperkalemia: Concomitant use of valsartan with drugs that increase potassium (eg, potassium-sparing diuretics) or salt substitutes containing potassium may lead to increased serum potassium and in heart failure patients to increases in serum creatinine.

NSAIDs: Monitor renal function periodically in patients receiving valsartan and non-steroidal anti-inflammatory drugs (NSAIDS) who are also elderly, volume-depleted (including those on diuretics), or who have compromised renal function due to potential reversible deterioration of renal function, including acute renal failure.

Important considerations due to the hydrochlorothiazide component in DIOVAN HCT and EXFORGE HCT: Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Hypersensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Lithium generally should not be given with thiazides. Thiazides have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Patients taking DIOVAN HCT or EXFORGE HCT should be observed for clinical signs of fluid or electrolyte imbalance. Monitor serum electrolytes periodically based on factors such as renal function, other medications, or history of prior electrolyte imbalances.

HCTZ, a sulfonamide, can cause an idiosyncratic reaction resulting in transient myopia and angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Discontinue HCTZ as rapidly as possible in these patients. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Common AEs: The most common adverse reactions that occurred more frequently with DIOVAN than placebo were viral infection (3% vs 2%), fatigue (2% vs 1%), and abdominal pain (2% vs 1%).

The most common adverse reaction that occurred more frequently with DIOVAN HCT than placebo was nasopharyngitis (2.4% vs 1.9%).

The most common adverse reactions that occurred more frequently with EXFORGE than placebo were peripheral edema (5% vs 3%), nasopharyngitis (4% vs 2%), upper respiratory tract infection (3% vs 2%), and dizziness (2% vs 1%).

The most frequent adverse events that occurred in ≥2% of patients treated with EXFORGE HCT were dizziness (8.2%), edema (6.5%), headache (5.2%), dyspepsia (2.2%), fatigue (2.2%), muscle spasms (2.2%), back pain (2.1%), nausea (2.1%), and nasopharyngitis (2.1%).

ADDITIONAL IMPORTANT SAFETY INFORMATION FOR TEKTURNA AND TEKTURNA HCT:

TEKTURNA HCT is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with aliskiren and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACE inhibitors or angiotensin receptor antagonists. Discontinue TEKTURNA or TEKTURNA HCT immediately in patients who develop angioedema, and do not readminister.

Hypotension: Excessive hypotension in patients with uncomplicated hypertension was seen rarely (0.1%) in patients treated with TEKTURNA alone and (<1%) in patients treated with TEKTURNA HCT. Hypotension was also infrequent during combination therapy with other antihypertensive agents (<1%). Volume- and/or salt-depletion should be corrected in patients before administering TEKTURNA or TEKTURNA HCT or symptomatic hypotension may occur. Patients taking TEKTURNA or TEKTURNA HCT should be observed for clinical signs of fluid or electrolyte imbalance.

Renal Considerations: Caution should be exercised when dosing TEKTURNA in patients with severe renal impairment (GFR <30 mL/min), as clinical experience with such patients is limited. Consider periodic determinations of serum electrolytes to detect possible imbalances, particularly in patients with severe renal impairment. TEKTURNA HCT is not recommended in patients with severe renal impairment.

Hyperkalemia: Increases were seen in serum potassium when TEKTURNA was used in combination with an ACE inhibitor (5.5%) in hypertensive diabetic patients. Routine monitoring of electrolytes and renal function is indicated in this patient population. Use caution when coadministering TEKTURNA or TEKTURNA HCT with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels.

Cyclosporine, Itraconazole, or Lithium: Avoid use of TEKTURNA or TEKTURNA HCT with cyclosporine or itraconazole. Additionally, avoid use of TEKTURNA HCT with lithium.

Furosemide: When aliskiren was coadministered with furosemide, the AUC and C_max of furosemide were reduced by about 30% and 50%, respectively. Patients receiving furosemide could find its effect diminished after starting aliskiren.

Important Considerations Due to the Hydrochlorothiazide Component: Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease. Thiazides should be used with caution in patients with severe renal disease, as they may precipitate azotemia. Thiazides have been reported to cause exacerbation or activation of systemic lupus erythematosus. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in those with such a history.

HCTZ, a sulfonamide, can cause an idiosyncratic reaction resulting in transient myopia and angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Discontinue HCTZ as rapidly as possible in these patients. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Common AEs: Adverse events with increased rates for TEKTURNA compared with placebo included: diarrhea (2.3% vs 1.2%), cough (1.1% vs 0.6%), rash (1.0% vs 0.3%), elevated uric acid (0.4% vs 0.1%), gout (0.2% vs 0.1%), and renal stones (0.2% vs 0%).

Adverse events with increased rates for TEKTURNA HCT compared with placebo included: dizziness (2.3% vs 1.0%), influenza (2.3% vs 1.6%), diarrhea (1.6% vs 0.5%), cough (1.3% vs 0.5%), vertigo (1.2% vs 0.5%), asthenia (1.2% vs 0%), and arthralgia (1.0% vs 0.5%).

ADDITIONAL IMPORTANT SAFETY INFORMATION FOR TEKAMLO:

Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with aliskiren and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACE inhibitors (ACEI) or angiotensin receptor antagonists. Discontinue TEKAMLO immediately in patients who develop angioedema, and do not readminister.

Hypotension: Excessive hypotension was seen rarely (0.2%) in patients with uncomplicated hypertension treated with TEKAMLO in controlled trials. Volume- and/or salt-depletion should be corrected in patients prior to administration of TEKAMLO or symptomatic hypotension may occur.

Risk of MI or Angina: Rarely, initiation or change to the dose of a calcium channel blocker has resulted in the increased frequency, duration, or severity of angina or acute myocardial infarction, particularly in patients with severe obstructive coronary artery disease.

Renal Considerations: Clinical trials with TEKAMLO and aliskiren in hypertension excluded patients with severe renal dysfunction (GFR <30 mL/min). Consider periodic determinations of serum electrolytes to detect possible imbalances.

No data are available on the use of TEKAMLO or aliskiren in patients with unilateral or bilateral renal artery stenosis. In studies of ACEIs in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported.

Hepatic Considerations: Use caution when administering TEKAMLO to patients with severe hepatic impairment, as amlodipine is extensively metabolized by the liver and the plasma elimination half-life is 56 hours in patients with impaired hepatic function.

Patients With Heart Failure: Titrate TEKAMLO slowly in patients with heart failure.

Hyperkalemia: Increases in serum potassium
>5.5 mEq/L were seen (5.5%) when aliskiren was used in combination with an ACEI in hypertensive diabetic patients. Monitor electrolytes and renal function in this population. Use caution when coadministering TEKAMLO with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels.

Cyclosporine or Itraconazole: Avoid use of TEKAMLO with cyclosporine or itraconazole.

Furosemide: When aliskiren was coadministered with furosemide, the AUC and C_max of furosemide were reduced by about 30% and 50%, respectively. Patients receiving furosemide could find its effect diminished after starting aliskiren.

Common AEs: The most common adverse event in a placebo-controlled trial that occurred in at least 2% of patients treated with TEKAMLO and at a higher incidence than placebo was peripheral edema (6.2% vs 1.0%). The incidence rate of peripheral edema at high dose was 8.9%.

ADDITIONAL IMPORTANT SAFETY INFORMATION FOR VALTURNA:

Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with aliskiren and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACE inhibitors (ACEIs) or angiotensin receptor antagonists. Discontinue aliskiren immediately in patients who develop angioedema, and provide appropriate therapy and monitoring until signs and symptoms resolve. Aliskiren should not be readministered.

Hypotension: In clinical trials, an excessive fall in blood pressure (hypotension) was seen rarely (<0.5%) in patients with uncomplicated hypertension treated with VALTURNA. Initiate therapy cautiously in patients with heart failure or recent myocardial infarction (MI) and in patients undergoing surgery or dialysis. Volume- and/or salt-depletion should be corrected in patients prior to administering VALTURNA or symptomatic hypotension may occur. Patients taking VALTURNA should be observed for clinical signs of fluid or electrolyte imbalance.

Renal Considerations: Care should be used when dosing VALTURNA in patients with severe renal impairment. As a consequence of inhibiting the RAAS, changes in renal function may be observed in susceptible individuals (eg, patients with renal artery stenosis or severe heart failure). Patients with severe renal impairment were excluded from clinical trials with VALTURNA in hypertension.

In studies of ACEIs in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. 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 ACEIs should be anticipated.

In patients with severe heart failure whose renal function may depend on the activity of the RAAS, treatment with ACEIs and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure or death. Similar outcomes have been reported with valsartan.

Hepatic Considerations: As a majority of valsartan is eliminated in the bile, valsartan should be used with care in patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, because of lower valsartan clearance.

Patients With CHF or Post-MI: Include assessment of renal function when evaluating patients with heart failure or post MI. Dosage reduction and/or discontinuation of a diuretic and/or valsartan may be required.

Hyperkalemia: In short-term controlled trials of VALTURNA, the incidence of hyperkalemia
(K+ >5.5 mEq/L) was about 1%-2% higher than with corresponding monotherapies or placebo. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk for hyperkalemia such as those with renal impairment. Concomitant use of VALTURNA with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels may lead to increases in serum potassium.

Cyclosporine or Itraconazole: Avoid use of VALTURNA with cyclosporine or itraconazole.

Furosemide: When aliskiren was coadministered with furosemide, the AUC and C_max of furosemide were reduced by about 30% and 50%, respectively. Patients receiving furosemide could find its effect diminished after starting aliskiren.

NSAIDs: Monitor renal function periodically in patients receiving valsartan and NSAIDs who are elderly, volume-depleted (including those on diuretics), or who have compromised renal function due to potential reversible deterioration of renal function, including acute renal failure.

Common AEs: The most common adverse events (AEs) that occurred more frequently with VALTURNA than placebo were fatigue (2.6% vs 1.4%), nasopharyngitis (2.6% vs 2.2%), diarrhea (1.4% vs 0.9%), upper respiratory tract infection (1.4% vs 1.1%), urinary tract infection (1.4% vs 0.6%), influenza (1.1% vs 0.2%), and vertigo (1.1% vs 0.3%).