Valsartan is an angiotensin II receptor blocker (ARB) indicated for: Hypertension in adults and children six years and older, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1.1 ) Heart failure (NYHA class II-IV); Valsartan oral solution significantly reduces hospitalization for heart failure in patients who are unable to swallow valsartan tablets ( 1.2 ) Stable left ventricular failure or left ventricular dysfunction following myocardial infarction; Valsartan oral solution reduces cardiovascular mortality in patients who are unable to swallow valsartan tablets ( 1.3 )
1.1Hypertension
Valsartan is indicated for the treatment of hypertension in adults and children six years and older, 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 the class to which valsartan principally belongs.
There are no controlled trials in hypertensive patients demonstrating risk reduction with valsartan. 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. Valsartan may be used alone or in combination with other antihypertensive agents.
1.2Heart Failure
Valsartan oral solution is indicated for the treatment of heart failure (NYHA class II-IV) to reduce the risk of hospitalization for heart failure in patients who are unable to swallow valsartan tablets. There is no evidence that valsartan provides added benefits when it is used with an adequate dose of an ACE inhibitor [see Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ].
1.3Post-Myocardial Infarction
Valsartan oral solution is indicated to reduce the risk of cardiovascular death in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction who are unable to swallow valsartan tablets [see Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) and Clinical Studies (14.3) ].
Contraindications
Do not use in patients with known hypersensitivity to any component. Do not coadminister aliskiren with valsartan oral solution in patients with diabetes [see Drug Interactions (7) ]. Known hypersensitivity ( 4 ) Patients with diabetes on aliskiren ( 4 )
Warnings and precautions
Observe for signs and symptoms of hypotension ( 5.2 ) Monitor renal function and potassium in susceptible patients ( 5.3 , 5.4 )
5.1Fetal Toxicity 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 valsartan oral solution as soon as possible [see Use in Specific Populations (8.1 )].
5.2Hypotension
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. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Peak plasma concentrations of valsartan are higher following administration of valsartan oral solution and may result in increased risk of hypotension as compared to administration of valsartan tablets [see Clinical Pharmacology (12.3) ].
Patients with heart failure or post-myocardial infarction patients given valsartan tablets in clinical trials commonly had some reduction in blood pressure. Only use valsartan oral solution in heart failure or post-myocardial infarction patients who are unable to swallow valsartan tablets. In clinical trials of valsartan tablets, discontinuation of therapy because of continuing symptomatic hypotension usually was not necessary.
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. If symptomatic hypotension occurs, place the patient in the supine position and, if necessary, give 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.
5.3Impaired 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 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 valsartan [see Drug Interactions (7) ].
5.4Hyperkalemia
Some patients with heart failure have developed increases in potassium. 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 valsartan oral solution may be required [see Adverse Reactions (6.1) ].
Interactions
Potassium-sparing diuretics, potassium supplements or salt substitutes may lead to increases in serum potassium, and in heart failure patients, increases in serum creatinine ( 7 ) NSAIDs increase risk of renal impairment and loss of antihypertensive effect ( 7 ) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia ( 7 ) Lithium: Increases in serum lithium concentrations and lithium toxicity ( 7 )
7.1Agents Increasing Serum Potassium
Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium- sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co- medication is considered necessary, monitor serum potassium.
7.2Non-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, coadministration 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.
7.3Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on valsartan oral solution and other agents that affect the RAS.
Do not coadminister aliskiren with valsartan oral solution in patients with diabetes. Avoid use of aliskiren with valsartan oral solution in patients with renal impairment (GFR < 60 mL/min).
7.4Lithium Increases
in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including valsartan. Monitor serum lithium levels during concomitant use.
Adverse reactions
Hypertension: Most common adverse reactions are headache, dizziness, fatigue and abdominal pain ( 6.1 ) Heart Failure: Most common adverse reactions are dizziness, hypotension, diarrhea, arthralgia, back pain, fatigue and hyperkalemia ( 6.1 ) Post-Myocardial Infarction: Most common adverse reactions which caused patients to discontinue therapy are hypotension, cough and increased blood creatinine ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd, at 866-488-0312 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Studies 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 practice. Adult Hypertension Valsartan has been evaluated for safety in more than 4,000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year.
Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with valsartan was similar to placebo. The overall frequency of adverse reactions was neither dose-related nor related to gender, age, race, or regimen. Discontinuation of therapy due to side effects was required in 2.3% of valsartan patients and 2.0% of placebo patients.
The most common reasons for discontinuation of therapy with valsartan were headache and dizziness. The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with valsartan and at a higher incidence in valsartan (n=2,316) than placebo (n=888) patients included fatigue (2% vs. 1%) and abdominal pain (2% vs. 1%). Headache, dizziness, upper respiratory infection, cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and arthralgia occurred at a more than 1% rate, but at about the same incidence in placebo and valsartan patients.
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).
Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence of dizziness was observed in patients treated with valsartan 320 mg (8%) compared to 10 to 160 mg (2% to 4%). Valsartan has been used concomitantly with hydrochlorothiazide without evidence of clinically important adverse interactions. Other adverse reactions that occurred in controlled clinical trials of patients treated with valsartan (>0.2% of valsartan patients) are listed below.
It cannot be determined whether these events were causally related to valsartan. Body as a Whole: Allergic reaction and asthenia Cardiovascular: Palpitations Dermatologic: Pruritus and rash Digestive: Constipation, dry mouth, dyspepsia, and flatulence Musculoskeletal: Back pain, muscle cramps, and myalgia Neurologic and Psychiatric: Anxiety, insomnia, paresthesia, and somnolence Respiratory: Dyspnea Special Senses: Vertigo Urogenital: Impotence Other reported events seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema.
Pediatric Hypertension Valsartan has been evaluated for safety in over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years. No relevant differences were identified between the adverse experience profile for pediatric patients aged 6 to 16 years and that previously reported for adult patients. Headache and hyperkalemia were the most common adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively.
Hyperkalemia was mainly observed in children with underlying renal disease. Neurocognitive and developmental assessment of pediatric patients aged 6 to 16 years revealed no overall clinically relevant adverse impact after treatment with valsartan for up to 1 year. Valsartan is not recommended for pediatric patients under 6 years of age. In a study (n=90) of pediatric patients (1 to 5 years), two deaths and three cases of on-treatment transaminase elevations were seen in the one-year open-label extension phase.
These 5 events occurred in a study population in which patients frequently had significant co-morbidities. A causal relationship to valsartan has not been established. In a second study of 6-months duration in 75 children aged 1 to 5 years, there were no deaths; one case of marked liver transaminase elevations occurred following 6 months of treatment. Heart Failure The adverse experience profile of valsartan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients.
In the valsartan Heart Failure Trial, comparing valsartan in total daily doses up to 320 mg (n=2,506) to placebo (n=2,494), 10% of valsartan patients discontinued for adverse reactions vs. 7% of placebo patients. The table shows adverse reactions in double-blind short-term heart failure trials, including the first 4 months of the valsartan Heart Failure Trial, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients.
All patients received standard drug therapy for heart failure, frequently as multiple medications, which could include diuretics, digitalis, beta-blockers. About 93% of patients received concomitant ACE inhibitors. Valsartan (n=3,282) Placebo (n=2,740) Dizziness 17% 9% Hypotension 7% 2% Diarrhea 5% 4% Arthralgia 3% 2% Fatigue 3% 2% Back Pain 3% 2% Dizziness, postural 2% 1% Hyperkalemia 2% 1% Hypotension, postural 2% 1% Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following: elevations in creatinine and elevations in potassium.
Other adverse reactions with an incidence greater than 1% and greater than placebo included headache, nausea, renal impairment, syncope, blurred vision, upper abdominal pain and vertigo. From the long-term data in the valsartan Heart Failure Trial, there did not appear to be any significant adverse reactions not previously identified. Post-Myocardial Infarction The safety profile of valsartan was consistent with the pharmacology of the drug and the background diseases, cardiovascular risk factors, and clinical course of patients treated in the post-myocardial infarction setting.
The table shows the percentage of patients discontinued in the valsartan and captopril-treated groups in the valsartan in Acute Myocardial Infarction Trial (VALIANT) with a rate of at least 0.5% in either of the treatment groups. Discontinuations due to renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients. Valsartan (n=4,885) Captopril (n=4,879) Discontinuation for adverse reaction Adverse reactions 5.8% 7.7% Hypotension NOS 1.4% 0.8% Cough 0.6% 2.5% Blood creatinine increased 0.6% 0.4% Rash NOS 0.2% 0.6% In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of valsartan.
Creatinine: Minor elevations in creatinine occurred in 0.8% of patients taking valsartan and 0.6% given placebo in controlled clinical trials of hypertensive patients. In heart failure trials, 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
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Composition
Active ingredients
VALSARTAN 4MG/ML
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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