Label: VALSARTAN solution

  • NDC Code(s): 70954-310-10, 70954-310-20
  • Packager: Novitium Pharma LLC
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated November 5, 2021

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use VALSARTAN ORAL SOLUTION safely and effectively. See full prescribing information for VALSARTAN ORAL SOLUTION.

    VALSARTAN oral solution
    Initial U.S. Approval: 1996

    WARNING:FETALTOXICITY
    See full prescribing information for complete boxed warning.
    • When pregnancy is detected, discontinue Valsartan Oral Solutionas soon as possible. (5.1)
    • Drugsthatactdirectlyon the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)
     



    INDICATIONS AND USAGE

    Valsartan isanangiotensinIIreceptorblocker (ARB) indicatedfor: (1)

    • Hypertension inadults andchildrensixyearsandolder,tolowerbloodpressure.Loweringbloodpressurereducestheriskoffatalandnonfatalcardiovascularevents,primarilystrokesandmyocardialinfarctions(1.1)
    • Heartfailure(NYHAclassII-IV); Valsartan oral solution significantly reduceshospitalizationforheartfailureinpatientswhoare unableto swallow valsartantablets(1.2)
    • Stableleftventricularfailureorleftventriculardysfunctionfollowingmyocardialinfarction; Valsartan oral solution reducescardiovascularmortalityin patients whoare unableto swallow valsartantablets(1.3)

    DOSAGE AND ADMINISTRATION


    Indication
    Starting Dose
    DoseRange
    TargetMaintenance Dose*
    Hypertension- adults (2.1)
    40 or 80 mg twice daily
    40 -160 mg twice daily
    ---
    Hypertension - age 6 to16
    years (2.2)
    0.65 mg/kg twice daily (up to 40 mg total)
    0.65-1.35 mg/kg twice daily (up to 40 mg-160 mg total)
    ---
    Heart Failure (2.3)
    40 mg twice daily
    40 mg-160 mg twice daily
    160 mg twice daily
    Post-Myocardial  Infarction (2.4)
    20 mg twice daily
    20 mg to 160 mg twice daily
    160 mg twice daily

    *as tolerated by patient (2)

    DOSAGE FORMS AND STRENGTHS

    Oral Solution, 4 mg/mL (3) (3)

    CONTRAINDICATIONS

    Known hypersensitivity(4) (4)

    Patients with diabetes on aliskiren (4) (4)

    WARNINGS AND PRECAUTIONS

    Observe for signs and symptoms of hypotension (5.2) (5)

    Monitor renal function and potassium in susceptible patients (5.3, 5.4) (5)

    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 Novitium Pharma LLC at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG 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)

    USE IN SPECIFIC POPULATIONS

    Lactation: Breastfeeding not recommended. (8.2). (8)

    Pediatrics: Efficacy and safety data support use in 6-16 year old patients; use is not recommended in patients <6 years old (6.1, 8.4) (8)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 11/2021

  • Table of Contents
  • BOXED WARNING (What is this?)

    BOXED WARNING


    WARNING: FETAL TOXICITY
    • When pregnancy is detected, discontinue Valsartan Oral Solution 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 & USAGE

    1.1 Hypertension

    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.

    1.2 Heart 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)].

    1.3 Post-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)].

  • 2 DOSAGE & ADMINISTRATION

    2.1 General Considerations

    Valsartan Oral Solution is not therapeutically equivalent to the tablet formulation of Diovan. The peak concentration of valsartan with Valsartan Oral Solution is higher than with Diovan [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]. Follow dosing instructions given here.

    2.2 Adult Hypertension

    The recommended starting dose of Valsartan Oral Solution is 40 mg or 80 mg twice daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions in blood pressure may be started at 80 mg administered twice a day. Valsartan Oral Solution may be used over a total daily dose range of 80 mg to 320 mg.


    The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If additional antihypertensive effect is required over the starting dose range, the total daily dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg.


    No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment, or for patients with mild or moderate liver insufficiency. Monitor closely patients with severe hepatic or renal impairment.


    Valsartan Oral Solution may be administered with other antihypertensive agents.

    2.3 Pediatric Hypertension 6 to 16 Years of Age

    Therecommended starting doseis0.65mg/kg twicedaily(upto40mg total dailydose).Thedosageshould be adjustedaccording tobloodpressureresponse. Doseshigherthan 1.35 mg/kg twicedaily(or>160mg total dailydose) have not beenstudiedinpediatricpatients 6 to 16 yearsold.

    Nodataareavailableinpediatricpatientseitherundergoingdialysisorwitha glomerular filtration rate <30 mL/min/1.73m2 [seeUseinSpecificPopulations(8.4)].

    Valsartan Oral Solutionisnot recommended forpatients under 6 yearsofage[seeAdverseReactions(6.1),UseinSpecificPopulations(8.4),ClinicalStudies(14.1)].

    2.4 Heart Failure

    The recommended starting dose of Valsartan Oral Solution is 40 mg twice daily. Titrate to 80 mg and 160 mg twice daily, as tolerated by the patient. Consider reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses.

    2.5 Post-Myocardial Infarction

    Valsartan Oral Solution may be initiated as early as 12 hours after a myocardial infarction. The recommended starting dose of Valsartan Oral Solution is 20 mg twice daily. Patients may be up titrated within 7 days to 40 mg twice daily, with subsequent titrations to a target maintenance dose of 160 mg twice daily, as tolerated by the patient. If symptomatic hypotension or renal dysfunction occurs, consider dosage reduction. Valsartan Oral Solution may be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin, beta-blockers, and statins.

  • 3 DOSAGE FORMS & STRENGTHS

    4 mg/mL aqueous solution

  • 4 CONTRAINDICATIONS

    Donot useinpatientswithknownhypersensitivitytoanycomponent.


    Donot coadminister aliskiren withValsartan Oral Solutioninpatientswithdiabetes[seeDrugInteractions(7)].

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Fetal 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)].

    5.2 Hypotension

    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.

    5.3 Impaired Renal Function

    Changesinrenalfunctionincludingacuterenalfailurecanbe caused by drugsthat inhibitthe renin- angiotensinsystemand by diuretics.Patientswhoserenalfunctionmaydependinpartontheactivityoftherenin-angiotensinsystem(e.g.,patientswithrenalarterystenosis, chronic kidneydisease,severecongestive heart failure,orvolume depletion)may be atparticularriskofdevelopingacuterenalfailureon valsartan. Monitorrenalfunctionperiodicallyinthese patients. Consider withholdingor discontinuingtherapyinpatientswhodevelop a clinically significantdecreaseinrenalfunctiononvalsartan[seeDrugInteractions(7)].

    5.4 Hyperkalemia

    Somepatientswithheart failurehave developedincreases inpotassium. Theseeffectsareusuallyminorand transient, andtheyaremore likelytooccurinpatientswithpre-existingrenalimpairment.Dosagereductionand/ordiscontinuationofValsartan Oral Solutionmay be required[seeAdverseReactions(6.1)].

  • 6 ADVERSE REACTIONS

    6.1 Clinical Studies Experience


    Becauseclinicalstudiesareconductedunder widely varying conditions,adversereactionratesobservedintheclinicalstudiesof a drugcannot be directlycompared toratesintheclinicalstudiesofanotherdrugandmay not reflecttheratesobservedinpractice.

    AdultHypertension

    Valsartanhas beenevaluatedforsafetyinmore than4,000 patients, includingover400treatedforover 6 months,andmore than160forover 1 year.Adversereactions have generally beenmildand transient innatureand have onlyinfrequentlyrequireddiscontinuationoftherapy.Theoverallincidenceofadversereactionswithvalsartanwassimilar toplacebo.


    Theoverallfrequency ofadversereactionswasneitherdose-related nor relatedtogender, age,race, orregimen. Discontinuationoftherapy due tosideeffectswasrequiredin 2.3% ofvalsartanpatientsand 2.0%ofplacebopatients. Themost common reasons fordiscontinuationof therapywithvalsartanwereheadacheanddizziness.


    Theadversereactionsthatoccurredinplacebo-controlled clinicaltrialsinatleast 1% ofpatientstreatedwithvalsartanandat a higherincidenceinvalsartan(n=2,316)thanplacebo(n=888)patientsincludedfatigue(2%vs.1%)andabdominalpain(2%vs.1%).


    Headache,dizziness,upperrespiratoryinfection,cough,diarrhea,rhinitis,sinusitis,nausea,pharyngitis,edema, andarthralgiaoccurred at a more than 1% rate, but atabout thesameincidenceinplaceboandvalsartan patients.


    Intrialsinwhichvalsartanwascompared toanACEinhibitorwithorwithoutplacebo,theincidenceofdrycoughwassignificantlygreaterintheACE-inhibitorgroup(7.9%)thaninthegroupswhoreceived valsartan(2.6%)orplacebo (1.5%). In a 129-patienttriallimited topatientswho had  drycoughwhenthey had previouslyreceivedACEinhibitors,theincidencesofcoughinpatientswhoreceived valsartan, HCTZ,orlisinopril were20%,19%,and69%respectively(p<0.001).


    Dose-relatedorthostaticeffectswereseeninlessthan1% of patients. Anincrease intheincidenceofdizzinesswasobservedinpatientstreatedwithvalsartan 320 mg(8%) compared to 10 to160mg(2%to4%).


    Valsartanhas beenusedconcomitantly withhydrochlorothiazidewithoutevidenceofclinically importantadverseinteractions.


    Otheradversereactionsthatoccurredincontrolled clinicaltrialsofpatientstreatedwithvalsartan(>0.2%ofvalsartan patients) arelistedbelow.Itcannot be determined whethertheseeventswerecausallyrelatedto valsartan.

    Bodyas a Whole: Allergicreactionandasthenia

    Cardiovascular:Palpitations

    Dermatologic:Pruritusandrash

    Digestive:Constipation,drymouth,dyspepsia,andflatulence

    Musculoskeletal:Backpain,muscle cramps, andmyalgia

    NeurologicandPsychiatric:Anxiety,insomnia,paresthesia,andsomnolence

    Respiratory:Dyspnea
    SpecialSenses:Vertigo
    Urogenital:Impotence

    Otherreportedeventsseenlessfrequentlyinclinicaltrialsincludedchestpain,syncope, anorexia,vomiting, andangioedema.

    Pediatric Hypertension

    Valsartanhas beenevaluatedforsafetyinover400pediatricpatientsaged 6 to 17 yearsandmore than160pediatricpatientsaged 6 months to 5 years.Norelevant differences wereidentifiedbetweentheadverseexperience profileforpediatricpatientsaged 6 to 16 yearsandthatpreviouslyreportedforadult patients. Headacheandhyperkalemia werethemost common adverseeventssuspectedto be studydrug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively.Hyperkalemia wasmainlyobservedinchildrenwithunderlyingrenaldisease.

    Neurocognitive anddevelopmental assessment ofpediatricpatientsaged 6 to 16 yearsrevealednooverallclinically relevant adverseimpact aftertreatmentwithvalsartanfor up to 1 year.

    Valsartanisnot recommended forpediatricpatients under 6 yearsofage.In a study(n=90)ofpediatricpatients(1to 5 years), two deathsandthreecasesofon-treatment transaminaseelevationswereseenintheone-year open-labelextensionphase.These 5 eventsoccurredin a studypopulationinwhichpatientsfrequently had significantco-morbidities. A causalrelationshiptovalsartan has not beenestablished.In a second studyof6-months durationin 75 childrenaged 1 to 5 years,therewerenodeaths; one caseofmarkedlivertransaminaseelevationsoccurredfollowing 6 months oftreatment.

    HeartFailure

    Theadverseexperience profileofvalsartaninheart failurepatientswasconsistentwiththepharmacology ofthedrugandthehealthstatusofthe patients. IntheValsartanHeartFailureTrial,comparing valsartanin total dailydoses up to 320 mg(n=2,506)toplacebo(n=2,494),10%ofvalsartanpatientsdiscontinuedforadversereactionsvs. 7% ofplacebo patients.

    Thetable showsadversereactionsindouble-blindshort-termheartfailuretrials,includingthefirst 4 months oftheValsartanHeart FailureTrial,withanincidenceofatleast 2% thatweremore frequentinvalsartan-treatedpatientsthaninplacebo-treated patients. Allpatientsreceived standard drugtherapyforheartfailure,frequentlyasmultiplemedications, whichcouldincludediuretics,digitalis,beta-blockers. About93%ofpatientsreceivedconcomitant ACEinhibitors.


     
    Valsartan (n=3,282)
    Placebo(n=2,740)
    Dizziness
    17%
    9%
    Hypotension
    7%
    2%
    Diarrhea
    5%
    4%
    Arthralgia
    3%
    2%
    Fatigue
    3%
    2%
    BackPain
    3%
    2%
    Dizziness,postural
    2%
    1%
    Hyperkalemia
    2%
    1%
    Hypotension,postural
    2%
    1%

    Discontinuationsoccurredin0.5%ofvalsartan-treatedpatientsand0.1%ofplacebopatientsforeachofthefollowing: elevationsincreatinineandelevationsinpotassium.

    Otheradversereactionswithanincidencegreaterthan1% andgreaterthanplaceboincludedheadache,nausea,renalimpairment,syncope, blurredvision,upperabdominalpainandvertigo.

    Fromthelong-term dataintheValsartanHeart FailureTrial,theredid not appearto be anysignificantadversereactions not previouslyidentified.

    Post-Myocardial Infarction

    Thesafetyprofileofvalsartanwasconsistentwiththepharmacology ofthedrugandthebackgrounddiseases,cardiovascularriskfactors,andclinicalcourseofpatientstreatedinthepost-myocardial infarctionsetting.The table showsthepercentageofpatientsdiscontinuedinthevalsartanandcaptopril-treatedgroupsintheValsartaninAcuteMyocardialInfarctionTrial(VALIANT)with a rate ofatleast0.5%ineitherofthetreatmentgroups.

    Discontinuationsdue torenaldysfunctionoccurredin 1.1% ofvalsartan-treatedpatientsand0.8%ofcaptopril-treated patients.


     
    Valsartan (n=4,885)
    Captopril (n=4,879)
    Discontinuation for adverse reaction
    5.8%
    7.7%
    Adverse reactions
    Hypotension NOS
    1.4%
    0.8%
    Cough
    0.6%
    2.5%
    Blood creatinine increased
    0.6%
    0.4%
    Rash NOS
    0.2%
    0.6%

    Incontrolled clinicaltrials, clinically importantchangesin standard laboratoryparameters wererarelyassociatedwithadministration of valsartan.

    Creatinine:Minorelevationsincreatinineoccurredin0.8%ofpatientstakingvalsartan and0.6%givenplaceboincontrolled clinicaltrialsofhypertensive patients. Inheartfailuretrials,greaterthan50%increases increatininewereobservedin3.9%ofvalsartan-treatedpatientscompared to0.9%ofplacebo-treated patients. Inpost-myocardial infarction patients, doublingofserumcreatininewasobservedin4.2%ofvalsartan-treatedpatientsand3.4%ofcaptopril-treated patients.

    HemoglobinandHematocrit:Greaterthan20%decreasesinhemoglobin andhematocrit wereobservedin0.4%and0.8%,respectively,ofvalsartan patients, compared with0.1%and0.1%inplacebo-treated patients.

    LiverFunctionTests:Occasional elevations(greaterthan150%)ofliverchemistries occurredinvalsartan-treated patients. Threepatients(<0.1%)treatedwithvalsartandiscontinuedtreatmentforelevatedliverchemistries.

    Neutropenia:Neutropeniawasobservedin1.9%ofpatientstreatedwithvalsartanand0.8%ofpatientstreatedwithplacebo.

    Serum Potassium:In hypertensivepatients, greaterthan20%increases inserumpotassiumwereobservedin4.4%ofvalsartan-treatedpatientscompared to2.9%ofplacebo-treated patients. Inheartfailure patients, greaterthan20%increases inserumpotassiumwereobservedin10.0%of valsartan- treatedpatientscompared to 5.1% ofplacebo-treated patients.

    Blood UreaNitrogen(BUN):Inheart failuretrials,greaterthan50%increases inBUNwereobservedin16.6%ofvalsartan-treatedpatientscompared to6.3%ofplacebo-treated patients.


    6.2 Postmarketing Experience


    Thefollowing additionaladversereactions have beenreportedinpostmarketingexperience:

    Hypersensitivity:There are rare reports of angioedema. 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 very rare reports of hepatitis

    Renal: Impaired renal function, renal failure

    ClinicalLaboratoryTests:Hyperkalemia

    Dermatologic:Alopecia, bullous dermatitis

    Blood andLymphatic:There are very rare reports of thrombocytopenia

    Vascular:Vasculitis

    Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

    Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or establish a causal relationship to drug exposure.

  • 7 DRUG INTERACTIONS

    7.1 Agents Increasing Serum Potassium

    Concomitant useofvalsartanwithotheragentsthat blocktherenin-angiotensinsystem, potassium-sparingdiuretics(e.g.,spironolactone, triamterene, amiloride), potassiumsupplements, saltsubstitutescontainingpotassiumorotherdrugsthatmayincrease potassiumlevels(e.g.,heparin)mayleadtoincreases inserumpotassiumandinheart failurepatientstoincreases inserumcreatinine.Ifco-medication isconsidered necessary, monitorserumpotassium.

    7.2 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

    Inpatientswhoareelderly,volume-depleted (including thoseondiuretictherapy),orwithcompromised renalfunction,coadministration ofNSAIDs,includingselectiveCOX-2inhibitors,withangiotensin IIreceptorantagonists,including valsartan, mayresultindeteriorationofrenalfunction,including

    possibleacuterenalfailure.Theseeffectsareusuallyreversible.Monitorrenalfunctionperiodicallyinpatientsreceiving valsartanandNSAIDtherapy.

    TheantihypertensiveeffectofangiotensinII receptorantagonists,includingvalsartan, may be attenuated by NSAIDsincludingselectiveCOX-2inhibitors.

    7.3 Dual 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).

    7.4 Lithium

    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.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    RiskSummary


    Valsartan Oral Solution 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. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Published reports include cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan(seeClinicalConsiderations). Studies in rats and rabbits with valsartan showed fetotoxicity only at maternally toxic doses(seeData).When pregnancy is detected, discontinue Valsartan Oral Solution as soon as possible.

    The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, respectively.

    ClinicalConsiderations


    Disease-associatedmaternal and/orembryo/fetalrisk

    Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

    Fetal/Neonataladversereactions

    Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

    In patients taking Valsartan Oral Solution during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories ofinuteroexposure to Valsartan Oral Solution for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of inuteroexposure to Valsartan Oral Solution, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

    Data


    AnimalData

    No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m2basis. Calculations assume an oral dose of 320 mg/day and a 60-kg patient.

    8.2 Lactation

    RiskSummary

    There are no data on the presence of Valsartan Oral Solution in human milk, the effects on the breastfed infant, or the effects on milk production. Valsartan is present in rat milk (see Data). Because of the potential for valsartan to affect postnatal renal development in nursing infants, advise a nursing woman not to breastfeed during treatment with Valsartan Oral Solution.

    Data

    Valsartanwasdetectedinthemilkoflactatingrats 15 minutesafteradministration of a 3 mg/kg dose.

    8.4 Pediatric Use

    Valsartan is not recommended for pediatric patients under 6 years of age due to safety findings for which a relationship to treatment could not be excluded [see Adverse Reactions (6.1)]. Furthermore, it is unknown whether post-natal use of valsartan before maturation of renal function is complete has long- term deleterious effects on the kidney. In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age.

    The antihypertensive effects of valsartan have been evaluated in two randomized, double-blind clinical studies in pediatric patients from 1-5 and 6-16 years of age [see Clinical Studies (14.1)]. The pharmacokinetics of valsartan have been evaluated in pediatric patients 1 to 16 years of age [see Clinical Pharmacology (12.3)]. Valsartan was generally well tolerated in children 6-16 years and the adverse experience profile was similar to that described for adults.


    In children and adolescents with hypertension where underlying renal abnormalities may be more common, renal function and serum potassium should be closely monitored as clinically indicated.

    No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m2.

    There is limited clinical experience with valsartan in pediatric patients with mild to moderate hepatic impairment [see Warnings and Precautions (5.3)].

    8.5 Geriatric Use

    Inthecontrolled clinicaltrialsof valsartan, 1,214 (36.2%)hypertensivepatientstreatedwithvalsartanwere≥65yearsand265(7.9%)were≥75years.Nooveralldifference intheefficacyorsafetyofvalsartanwasobservedin this patient population, but greatersensitivityofsome olderindividualscannot be ruledout.

    Ofthe2,511 patientswithheartfailurerandomized tovalsartanintheValsartanHeart FailureTrial,45%(1,141)were65yearsofageorolder.IntheValsartaninAcuteMyocardialInfarctionTrial(VALIANT), 53% (2,596)ofthe4,909patientstreatedwithvalsartanand 51% (2,515)ofthe4,885patientstreatedwithvalsartan + captoprilwere65yearsofageorolder.Therewereno notable differences inefficacyorsafetybetweenolderandyoungerpatientsineithertrial.

    8.6 Renal Impairment

    Safety and effectiveness of valsartan in patients with severe renal impairment (CrCl ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.

    8.7 Hepatic Impairment

    No dose adjustment is necessary for patients with mild-to-moderate liver disease. No dosing recommendations can be provided for patients with severe liver disease.

  • 10 OVERDOSAGE

    Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been reported. If symptomatic hypotension should occur, supportive treatment should be instituted.


    Valsartan is not removed from the plasma by hemodialysis.


    Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmosets, except for salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 31 times, respectively, the maximum recommended human dose on a mg/m2 basis). (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

  • 11 DESCRIPTION

    Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT1 receptor subtype.

    Valsartan is chemically described as N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine. Its empirical formula is C24H29N5O3, its molecular weight is 435.5, and its structural formula is:


    structure

    Valsartan is an off white to white powder. It is soluble in methanol.

    Valsartan Oral Solution is formulated at a concentration of 4 mg/mL valsartan, USP as a clear colorless, grape flavored solution, free from visible particulate matter for oral administration. The inactive ingredients are: grape flavor, methylparaben, poloxamer 188, potassium sorbate, propylene glycol, purified water, sodium citrate dihydrate, sodium hydroxide and sucralose.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

    There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself.

    Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

    Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.

    12.2 Pharmacodynamics

    Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available.

    Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed.

    In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.

    In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.

    12.3 Pharmacokinetics

    For an equivalent dose, Valsartan Oral Solution has 86% higher peak concentration (Cmax) and 25% higher area under the plasma concentration over time curve (AUC) for valsartan compared to Diovan. AUC and Cmax of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.

    AbsorptionValsartan Oral Solution Cmax is achieved 0.7 to 3.7 hours after dosing.

    Effect of Food

    High-fat, high-calorie meal decreased the AUC of Valsartan Oral Solution by about 8% and Cmax by about 44%.

    Distribution

    The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.

    Elimination

    Following intravenous administration, plasma clearance of valsartan is about 2 L/h. Renal clearance of valsartan is 0.62 L/h (about 30% of total body clearance). Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours.

    Metabolism

    The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and co-administered drugs are unlikely because of the low extent of metabolism.

    Excretion

    When administered as an oral solution, 83% of the dose is recovered in feces and about 13% is recovered in urine. The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.

    Special Populations:

    Geriatric Patients: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young.

    Pediatric Patients:  In a study of pediatric hypertensive patients (n=26, 1 to 16 years of age) given single doses of a suspension of valsartan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was similar to that of adults receiving the same formulation.

    Male and Female Patients: Pharmacokinetics of valsartan does not differ significantly between males and females.

    Heart Failure Patients: The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to those observed in healthy volunteers. AUC and Cmax values of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients.

    Patients with Renal Impairment: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, monitor closely [see Dosage and Administration (2.1)].

    Patients with Hepatic Impairment: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex, and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Monitor closely patients with liver disease [see Dosage and  Administration  (2.1)].

    Drug Interactions

    No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with nebivolol, amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin.


    Co-administration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time- course of the anticoagulant properties of warfarin.

    Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

    There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

    Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E. coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test.

    Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m2 basis.

     (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

    13.2 Animal Pharmacology & OR Toxicology

    Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10% of the maximum recommended pediatric dose on a mg/m2 basis) from postnatal day 7 to postnatal day 70 produced persistent, irreversible kidney damage. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life.

  • 14 CLINICAL STUDIES

    14.1 Hypertension

    Studies evaluating the antihypertensive effects of valsartan were conducted with a formulation that is not therapeutically equivalent to Valsartan Oral Solution [see Clinical Pharmacology (12.3)].

    Adult Hypertension

    The antihypertensive effects of valsartan were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (1 in patients over 65 years) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95-115 mmHg. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.

    Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.

    In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of valsartan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear.

    Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.

    The blood pressure-lowering effect of valsartan and thiazide-type diuretics are approximately additive.

    The 7 studies of valsartan monotherapy included over 2,000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80 to 160 mg and 9/6 mmHg at 320 mg. In a controlled trial the addition of HCTZ to valsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone.

    Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups.

    In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg.

    There are no trials of valsartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

    There was essentially no change in heart rate in valsartan-treated patients in controlled trials.

    Pediatric Hypertension

    The antihypertensive effects of valsartan were evaluated in two randomized, double-blind clinical studies.

    In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses). Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study. At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by -8, -10, -12 mmHg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was -4 and -7 mmHg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose- dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.

    In a clinical study involving 90 hypertensive pediatric patients 1 to 5 years of age with a similar study design, there was some evidence of effectiveness, but safety findings for which a relationship to treatment could not be excluded mitigate against recommending use in this age group [see Adverse Reactions (6.1)].

    14.2 Heart Failure


    TheValsartanHeartFailureTrial(Val-HeFT)wasa multinational,double-blindstudyinwhich5,010patientswithNYHAclassII(62%)toIV(2%)heartfailureandLVEF<40%,onbaselinetherapychosen by theirphysicians,wererandomized toplaceboorvalsartan (titrated from40mgtwicedailytothehighesttolerateddoseor160mgtwicedaily)andfollowedfor a meanofabout 2 years.TheVAL-HeFTstudywasconductedwith a formulation ofvalsartanthatis not therapeuticallyequivalenttoValsartan Oral Solution[seeClinical Pharmacology (12.3)].AlthoughVal-HeFT’sprimary goalwastoexaminetheeffectofvalsartanwhenaddedtoanACEinhibitor,about 7% were not receiving anACEinhibitor.Otherbackgroundtherapyincludeddiuretics(86%),digoxin(67%),andbeta-blockers (36%).Thepopulationstudiedwas80%male, 46%65yearsorolderand89%Caucasian.Attheendofthetrial,patientsinthevalsartangroup had a bloodpressurethatwas 4 mmHgsystolicand 2 mmHgdiastoliclowerthantheplacebogroup.Therewere two primary endpoints,bothassessedastimetofirstevent: all-causemortality andheart failuremorbidity, thelatterdefinedasall-causemortality, suddendeathwithresuscitation,hospitalizationforheartfailure,andtheneedforintravenousinotropicorvasodilatorydrugsforatleast 4 hours.Theseresultsaresummarized inthefollowing table.

     


     
    Placebo
    (N=2,499)
    Valsartan
    (N=2,511)
    Hazard Ratio
    (95%CI*)
    Nominal
    p-value
     
    All-cause mortality
     
     
    484
    (19.4%)
    495
    (19.7%)
    1.02
    (0.90-1.15)
    0.8
    HFmorbidity
    801
    (32.1%)
    723
    (28.8%)
    0.87
    (0.79-0.97)
    0.009

    *CI = Confidence Interval


    Althoughtheoverallmorbidity resultfavored valsartan, this resultwaslargelydriven by the 7% ofpatients not receiving anACEinhibitor,asshowninthefollowing table.



     
    Without ACE Inhibitor
    With ACE Inhibitor
     
    Placebo
    (N=181)
    Valsartan
    (N=185)
    Placebo
    (N=2,318)
    Valsartan
    (N=2,326)
    Events(%)
    77 (42.5%)
    46(24.9%)
    724 (31.2%)
    677(29.1%)
    Hazardratio(95%CI)
    0.51(0.35,0.73)
     
    0.92(0.82,1.02)
     
    p-value
    0.0002
     
    0.0965
     

    The modest favorable trend in the group receiving an ACE inhibitor was largely driven by the patients receiving less than the recommended dose of ACE inhibitor. Thus, there is little evidence of further clinical benefit when valsartan is added to an adequate dose of ACE inhibitor.

    Secondary end points in the subgroup not receiving ACE inhibitors were as follows.


     
    Placebo
    (N=181)
    Valsartan
    (N=185)
    Hazard Ratio
    (65% CI)
    Components of HF morbidity
     
     
     
    All-causemortality
    49(27.1%)
    32 (17.3%)
    0.59(0.37,0.91)
     
    Sudden deathwithresuscitation
    2 (1.1%)
    1 (0.5%)
    0.47(0.04,5.20)
     
    CHFtherapy
    1 (0.6%)
    0 (0.0%)

     
    CHFhospitalization
    48(26.5%)
    24 (13.0%)
    0.43(0.27,0.71)
     
    Cardiovascularmortality
    40(22.1%)
    29 (15.7%)
    0.65(0.40,1.05)
    Non-fatalmorbidity
    49(27.1%)
    24 (13.0%)
    0.42(0.26,0.69)

    In patients not receiving an ACE inhibitor, valsartan-treated patients had an increase in ejection fraction and reduction in left ventricular internal diastolic diameter (LVIDD).


    Effects were generally consistent across subgroups defined by age and gender for the population of patients not receiving an ACE inhibitor. The number of black patients was small and does not permit a meaningful assessment in this subset of patients.

    14.3 Post-Myocardial Infarction


    TheVALsartan In Acutemyocardial iNfarcTiontrial(VALIANT)was a randomized, controlled, multinational,double-blindstudyin14,703patientswithacutemyocardial infarctionandeitherheartfailure(signs,symptomsorradiologicalevidence) orleft ventricularsystolicdysfunction(ejectionfraction≤40% by radionuclideventriculographyor≤35% by echocardiographyorventricularcontrastangiography).TheVALIANTstudywasconductedwith a formulation ofvalsartanthatis not therapeuticallyequivalenttoValsartan Oral Solution[seeClinical Pharmacology (12.3)].Patientswererandomized within 12 hoursto 10 days aftertheonset ofmyocardial infarctionsymptomsto one ofthreetreatmentgroups:valsartan (titrated from 20 or40mgtwicedailytothehighesttolerateddose up to a maximumof160mgtwicedaily),theACEinhibitor,captopril (titrated from6.25mgthreetimesdailytothehighesttolerateddose up to a maximumof 50 mgthreetimesdaily),orthecombination ofvalsartanpluscaptopril.Inthecombination group,thedoseofvalsartanwastitratedfrom 20 mgtwicedailytothe highesttolerateddose up to a maximumof80mgtwicedaily;thedoseofcaptoprilwasthesameasformonotherapy. Thepopulationstudiedwas69%male, 94%Caucasian,and 53% were65yearsofageorolder.Baselinetherapyincludedaspirin(91%),beta-blockers (70%),ACEinhibitors(40%),thrombolytics (35%)andstatins(34%).Themeantreatmentdurationwas 2 years.Themeandailydoseofvalsartaninthemonotherapy groupwas 217 mg.

    Theprimary endpointwastimetoall-causemortality. Secondary endpoints included(1)timetocardiovascular(CV)mortality, and(2)timetothefirsteventofcardiovascularmortality, reinfarction,orhospitalizationforheart failure.Theresultsaresummarized inthefollowing table.




     
    Valsartan vs. Captopril (N=4,909) (N=4,909)
    Valsartan + Captopril vs. Captopril (N=4,885) (N=4,909)
    No. of Deaths
    Valsartan/
    Captopril
    Hazard
    Ratio
    CI
    p-value
    No. of Deaths
    Comb/Captopril
    Hazard Ratio
    CI
    p-value
    All-causemortality
     
    979(19.9%)
    /958(19.5%)
     
    1.001 (0.902,
    1.111)
    0.98
    941(19.3%)
    /958(19.5%)
     
    0.984
    (0.886,
    1.093)
     
    0.73
     
    CVmortality
    827 (16.8%)
    /830 (16.9%)
    0.976 (0.875, 1.090)
     
     
     
     
    CVmortality, hospitalizationforHF,andrecurrent non- fatal MI
     
    1,529 (31.1%)
    /1,567(31.9%)
     
    0.955
    (0.881,
    1.035)
     
     
     
     

    Therewasnodifference inoverallmortality among thethreetreatmentgroups.TherewasthusnoevidencethatcombiningtheACEinhibitorcaptoprilandtheangiotensinIIblocker valsartanwasofvalue.

    Thedatawereassessedtoseewhethertheeffectiveness ofvalsartancould be demonstrated by showingin a non-inferiorityanalysisthat it preserved a fractionoftheeffectofcaptopril, a drugwith a demonstrated survivaleffectin this setting. A conservativeestimateoftheeffectofcaptopril(basedon a pooledanalysisof 3 post-infarction studiesofcaptopriland 2 otherACEinhibitors)was a 14%to16%reductioninmortality compared toplacebo.Valsartanwould be considered effectiveifitpreserved a meaningfulfractionofthateffectandunequivocallypreservedsome ofthateffect.Asshowninthetable,theupper bound oftheCIforthehazardratio(valsartan/captopril)foroverallorCVmortality is1.09to 1.11, a difference ofabout9%to11%,thusmakingitunlikelythat valsartan has lessthanabouthalfoftheestimated effectofcaptoprilandclearlydemonstratinganeffectof valsartan. Theothersecondary endpoints wereconsistentwith this conclusion.


    study

    Therewerenocleardifferences inall-causemortality basedonage,gender, race,orbaselinetherapies,asshowninthefigureabove.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Valsartan Oral Solution containing 4 mg/mL valsartan, USP for oral administration is available as:


    White HDPE bottles containing 120 mL: NDC 70954-310-10


    White HDPE bottles containing 473 mL: NDC 70954-310-20


    Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C -30°C (59°F -86°F) [see USP Controlled Room Temperature].


    Dispense in tight container (USP).

  • 17 PATIENT COUNSELING INFORMATION


    FetalToxicity

    Advisepregnantwomen andfemales ofreproductivepotentialofthepotentialriskto a fetus.Advisefemales ofreproductivepotentialtonotifytheirhealthcareproviderwith a knownorsuspectedpregnancy[seeWarnings and Precautions(5.1)andUseinSpecificPopulations(8.1)].


    Lactation


    Advisewomen not tobreastfeedduringtreatmentwithValsartan Oral Solution [seeUseinSpecificPopulations(8.2)].

    SymptomaticHypotension


    Advisepatientsthat lightheadednesscanoccur,especiallyduringthefirstdays oftherapy,andthat itshould be reportedtotheprescribing physician.Tellpatientsthat ifsyncopeoccurstodiscontinueValsartan Oral Solution untilthephysician has beenconsulted.

    Cautionallpatientsthatinadequate fluidintake,excessiveperspiration,diarrhea,orvomitingcanleadtoanexcessivefallinbloodpressure,withthesameconsequences oflightheadednessandpossiblesyncope.


    Hyperkalemia

    Advisepatientsnot tousesaltsubstitutescontainingpotassiumwithoutconsultingtheirphysician.

    Trademarks are the property of their respective owners.


    Manufactured by:

    Novitium Pharma LLC

    70 Lake Drive, East Windsor

    New Jersey 08520


    Issued: 02/2021

    LB4202-01

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL


    Container label for 120mL
    container1
    Container label for 473mL
    container2

  • INGREDIENTS AND APPEARANCE
    VALSARTAN 
    valsartan solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:70954-310
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    VALSARTAN (UNII: 80M03YXJ7I) (VALSARTAN - UNII:80M03YXJ7I) VALSARTAN4 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    METHYLPARABEN (UNII: A2I8C7HI9T)  
    POLOXAMER 188 (UNII: LQA7B6G8JG)  
    POTASSIUM SORBATE (UNII: 1VPU26JZZ4)  
    SUCRALOSE (UNII: 96K6UQ3ZD4)  
    TRISODIUM CITRATE DIHYDRATE (UNII: B22547B95K)  
    WATER (UNII: 059QF0KO0R)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    Product Characteristics
    Color    Score    
    ShapeSize
    FlavorGRAPEImprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:70954-310-10120 mL in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product11/02/2021
    2NDC:70954-310-20473 mL in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product11/02/2021
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21410211/02/2021
    Labeler - Novitium Pharma LLC (080301870)
    Establishment
    NameAddressID/FEIBusiness Operations
    Novitium Pharma LLC080301870MANUFACTURE(70954-310) , PACK(70954-310)