NIASPAN 1000 MG EXTENDED RELEASE FILM COATED TABLETS

Israel - English - Ministry of Health

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Active ingredient:
NIACIN 1000 MG
Available from:
ABBOTT MEDICAL LABORATORIES LTD
ATC code:
C04AC01
Pharmaceutical form:
FILM COATED TABLETS - EXTENDED RELEASE
Administration route:
PER OS
Manufactured by:
ABBOTT LABORATORIES , USA
Therapeutic group:
NICOTINIC ACID
Therapeutic indications:
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hyperlipidemia. Niacin therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. 1.NIASPAN is indicated to reduce elevated TC, LDL-C, Apo B and TG levels, and to increase HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia. 2.NIASPAN in combination with simvastatin or lovastatin is indicated for the treatment of primary hyperlipidemia and mixed dyslipidemia when treatment with NIASPAN, simvastatin, or lovastatin monotherapy is considered inadequate. 3.In patients with a history of myocardial infarction and hyperlipidemia, niacin is indicated to reduce the risk of recurrent nonfatal myocardial infarction. 4.In patients with a history of coronary artery disease (CAD) and hyperlipidemia, n
Authorization number:
148473337300
Authorization date:
2012-08-01

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

17-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

17-01-2021

1986-ו"משתה)םירישכת(םיחקורהתונקתיפלןכרצלןולע

דבלב אפור םשרמ יפ לע תקוושמ הפורתה

ג"מ500ןפסאינ

ךשוממ רורחשב תופוצמ תוילבט

ג"מ750ןפסאינ

ךשוממ רורחשב תופוצמ תוילבט

ג"מ1000ןפסאינ

ךשוממ רורחשב תופוצמ תוילבט

ג"מ1000,ג"מ750,ג"מ500 Niacin - ןיצאינ - ליעפה רמוחה

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הפורתב שומישב תועגונה תודחוימ תורהזא

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םיחקלנםהרשאכןפסאינלשהתלועפתאקיספהלםילוכי

ףרשהתפורתלשןולעבןייעלשיףסונב.תוכימסבואדחיב

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.רתוי דוע םדה

שומיש.םידירצילגירטואלורטסלוכתדרוהלתורחאתופורת

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.ןיריפסא

ןוזמו לוהוכלא ,ןפסאינב שומיש

ףירחןוזמלוכאלואםימחתואקשמ,לוהוכלאתותשלאליוצר

תאתולעהלםילולעםהשםושמתאז.ןפסאינתליטנןמזלךומס

.דוריגו ) flushing ( הקמסה ןוגכ יאוול תועפותל יוכיסה

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ןפסאינשםושמתאז.הקינימךנהםאןפסאינבישמתשתלא

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.חוטב ךניא םא ךלש חקורה וא אפורה םע

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ךלץלמוהשהזמרישכתהלשםינונימהבולישתאתונשלןיא

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תוילבטה תא םילטונ ךיא

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ןוויכהעילבהינפלתוילבטהתאסעלתואקסרת,הצחתלא

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רתוי הובג ןונימ תועטב תלטנ םא

הנפ,הפורתהןמדליעלבתועטבםאוארתיתנמתלטנםא

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תורומרמצ,תושישת,באכ,תקצב

לשמל(ףוגהדוקפתבהעיגפלעםידיעמשםדהתוקידבבםייוניש

)השירק ידוקפת ,םירירש ,דבכ ידוקפת

תורידנ םיתיעל תועיפומה יאוול תועפות

)טואג(ןודגש

היסקרונא

תונבצע,הנישתויעב

תונרגימ

הייארשוטשט,םייניעבתויעב

תורחאבצקתוערפה,םירודזורפרופרפ:ןוגכתויבבלתויעב

םדץחלתת

תופלעתה

םייעמבואהביקבתומיוסמתויעב,םיקוהיגוא)תוחיפנ(םיזג

)םיביכ(

תבהצ

רועהלעםיהכםימתכוא)רתיתייצטנמגיפ(רועהלשתוהכתה

רועה עבצב יוניש וא

םיילגרבםירירשתויוצווכתה,םירירשתשלוח,םירירשבאכ

םינפבתקצב,הזחבבאכ

,תושישת,תיתקצבתלזנושוטיעלתמרוגהףאהתקלד-סיטיניר

תורומרמצ

תעפותמלבוסהתארשאכואהרימחמיאוולהתועפותמתחאםא

.אפורה םע ץעייתהל ךילע ,ןולעב הרכזוה אלש יאוול

?הפורתה תא ןסחאל ךיא.5

םוקמברומשלשיתרחאהפורתלכווזהפורת!הלערהענמ

ענמתךכידילעותוקוניתוא/וםידלילשםדיגשיהלץוחמחוטב

.הלערה

.אפורהמ תשרופמ הארוה אללהאקהל םורגל ןיא

םעפלכבהנמהותיוותהקודבלשי!ךשוחבתופורתלוטילןיא

קוקזךניהםאםייפקשמביכרהלשי.הפורתלטונךניהש

.םהל

עיפומה) exp . date (הגופתהךיראתירחאהפורתבשמתשהלןיא

ותואלשןורחאהםוילסחייתמהגופתהךיראת.הזיראהיבגלע

.תרחא ןייוצמ ןכ םא אלא ,שדוח

-ל תחתמ ןסחאלשי

.תוחל ינפמ ןגהל ידכ בטיההרוגסהזיראהתארומש

ףסונ עדימ.6

- םג הליכמ הפורתה ליעפה רמוחהלעףסונ

Hypromellose,Povidone,StearicAcid,andthefollowing

coloringagents:FD&Cyellow#6/sunsetyellowFCF

AluminumLake,RedandYellowIronOxides,Polyethylene

Glycol, Hypromellose and Titanium Dioxide

:הזיראהןכותהמוהפורתהתיארנדציכ

וקאלל,ינוניבלדוגב,המותכ,הפוצמהילבטאיהןפסאינ

.היצח

םיקובקבבתועיגמג"מ1000-וג"מ750,ג"מ500ןפסאינתוילבט

.דחא לכ תוילבט90וא30םיליכמה

.םיקוושמ )90וא30( הזיראה ילדג לכ אל

.ב"הראטובאתודבעמ:ןרציהםש

ד.ת,מ"עבתויאופרתודבעמטובא:ותבותכוםושירהלעב

.61580ביבא-לת ,58099

.תואירבהדרשמי"ערשואוקדבנהזןולע

דרשמביתכלממהתופורתהסקנפבהפורתהםושיררפסמ

:תואירבה

148-45-33369-00:ג"מ500ןפסאינ

148-46-33371-00:ג"מ750ןפסאינ

148-47-33373-00:ג"מ1000ןפסאינ

לע.רכזןושלבחסונהזןולע,האירקהתלקהלותוטשפהםשל

.םינימה ינש ינבל תדעוימ הפורתה ,תאז ףא

SH NIA APL Aug 2012

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

Themedicineisdispensedbyphysician’sprescriptiononly

Niaspan ® 500 mg

Extended-ReleaseFilm-CoatedTablets

Niaspan ® 750 mg

Extended-ReleaseFilm-CoatedTablets

Niaspan ® 1000 mg

Extended-ReleaseFilm-CoatedTablets

Active Ingredient - Niacin 500 mg, 750 mg, 1000 mg

Foralistoftheinactiveingredients–seesection6inthis

leaflet.

Readtheentireleafletcarefullybeforeyouusethis

medicine.Thisleafletcontainsconciseinformationaboutthe

medicine.Ifyouhavefurtherquestions,refertothedoctor

or pharmacist.

Thismedicinehasbeenprescribedforthetreatmentofyour

ailment.Donotpassitontoothers.Itmayharmthem,even

ifitseemstoyouthattheirailmentissimilar.Niaspanis

intendedforadultsonly.Itisnotrecommendedforchildren

or adolescents.

1.WHAT IS THISMEDICINEINTENDEDFOR?

Niaspan is intended for regulation of blood fats (lipids).

Themedicineisprovidedasacontrolled-releasetablet.

Thismeansthattheactiveingredientisreleasedslowlyover

time.

Niaspanworkstoincreasethe'good'cholesterol(HDL)levels

andtodecreasethelevelsof'bad'cholesterol(LDL)and

triglycerides in your blood.

Regulatingthelevelsoffats(lipids)inyourbloodisimportant

to keep your heart and blood vessels healthy.

Niaspancanbegivenaloneorincombinationwithother

cholesterol-lowering medicines.

Niaspancannotreplacethebenefitsofahealthylifestyle.Tryto

keep a balanced, low-fat diet and take regular exercise.

Niaspan contains niacin (nicotinic acid).

Niaspan tablets release the niacin slowly.

Therapeuticgroup:Niacin(nicotinicacid),amedicinefor

regulating fat (lipid) levels.

2.BEFORE USING THE MEDICINE

Do not use the preparation if:

you are sensitive or allergic to niacin (nicotinic acid) or to

anyoftheotheringredientscontainedinthemedicine(for

alistoftheadditionalingredientsseesection6:Further

information).

you suffer from a liver problem or liver disease.

you suffer from an ulcer in your stomach or intestines.

you suffer from bleeding.

Tellthedoctorifoneoftheabovementionedconditions

applies to you.

Special warnings regarding use of this medicine

Tell the doctor if:

you are pregnant or plan to get pregnant.

you are breastfeeding or are planning to breastfeed.

you have ever had liver problems that may have caused

youreyesorskintogoyellow(jaundice),causednausea,

causedahighfever,ormadeyoufeelgenerallyunwellor

madeyoururinedarkerthanusual.Youmayneedtohave

blood tests before and during treatment.

you consume substantial quantities of alcohol.

you have or have had kidney problems.

you have or have had muscle problems.

you have or have had chest pains (unstable angina) or have

recentlyhadaheartattack,particularlyifyouaretaking

additionalmedicinestolowerbloodpressure(seelistbelow

inthesection“Ifyouaretaking,orhaverecentlytaken,other

medicines”).

you have diabetes. You may need to check blood sugar

levelsmoreoften,becauseNiaspancanincreaseblood

sugarlevels.Youmayneedtoconsultthedoctorregardinga

changeinyourdiet,insulindosageordiabetesmedicines.

you have or ever have had gout. The level of uric acid in

you have or have had a reduction in the levels of phosphorus

inyourblood.Thedoctormaywanttoperformbloodtests

in order to monitor your blood phosphorus levels.

you have had an ulcer in your stomach or intestines,

jaundice, liver or gallbladder disease.

you are scheduled to undergo operation, tell the doctor that

you take Niaspan. Niaspan may affect blood clotting.

Ifyouaretaking,orhaverecentlytaken,othermedicines

includingnon-prescriptionmedicines,herbalmedicines

andnutritionalsupplements,tellthedoctororpharmacist.

Particularly tell the doctor or pharmacist if you are taking:

Medicines for diabetes, including insulin - you may need to

checkyourbloodsugarlevelsmoreoften.Youmayneedto

talkwithyourdoctorregardingapossiblechangeinyour

diet or in the dosage of your diabetes medicines.

Medicines to thin the blood - you may need to have blood

tests more often.

Medicines called resins (bile acid sequestrants) – take them

atleast4-6hoursbeforetakingNiaspan.Thisisbecause

resinsmaystopNiaspanactionwhentakentogetheror

closetoeachother.Alsoseethepackageleafletofthe

resin medicine (bile acid sequestrants).

Medicines which lower blood pressure, such as nicotine

patches,nitrates,calciumchannelblockersorbeta-blockers.

Niaspan may lower the blood pressure even more.

Other medicines for lowering cholesterol or triglycerides.

UseofNiaspantogetherwithstatins(cholesterol-lowering

medicines)increasestheriskofmuscledamage,especially

intheolderpopulation,diabetespatients,patientssuffering

fromkidneyfailureorpatientswithanuncontrolled

hypothyroidism.

Aspirin.

Taking Niaspan with alcohol and food

Itisrecommended nottodrinkalcohol,hotdrinksoreatspicy

foodclosetothetimeyoutakeNiaspan.Thisisbecause

theycanincreasetheriskofsideeffectssuchasflushing

anditching.Drinkingalcoholheavilyatanytimewhiletaking

Niaspan may increase the risk of liver damage.

Pregnancy and breastfeeding

If you are pregnant or planning to become pregnant, talk

to your doctor before you take Niaspan.

Do not take Niaspan if you are breastfeeding. This is

because Niaspan may pass into the breast milk.

Driving and using machines

Niaspanisnotlikelytoaffectyourabilitytodriveoroperate

machines.

3.HOW SHOULD YOU TAKE NIASPAN?

AlwaystakeNiaspanaccordingtothedoctor’sinstructions.

Check with your doctor or pharmacist if you are not sure.

Your doctor will start giving you a low dose and will gradually

increaseit.Increasingthedosagedependsonhowthe

medicine affects you.

Do not change the combination of dosages of the

preparationfromthatrecommendedtoyoubythedoctor.

Donotdiscontinuetreatmentwithoutconsultingthe

doctor.

Do not replace Niaspan preparations with sustained-release

niacinpreparationsorwithequivalentdosesofimmediate-

release(crystalline)niacinwithoutinstructionfromthe

doctor. This can cause liver damage.

How to take the tablets

Take Niaspan at bedtime.

Take Niaspan after a low-fat snack, e.g.: an apple, low-fat

yoghurtorasliceofbread.TakingNiaspanonanempty

stomach is not recommended.

Donotdivide,crush,orchewthetabletsbeforeswallowing,

since they are extended release tablets.

Swallow the tablets whole with water.

If you have accidently take a higher dosage

If you have taken an overdose or if a child has accidentally

swallowedthemedicine,proceedimmediatelytoadoctor

orahospitalemergencyroomandbringthepackageofthe

medicine with you.

If you forget to take the Niaspan tablets

Do not take a double dose to make up for a forgotten dose.

Take your usual dose the next evening.

Adhere to the Niaspan treatment as recommended by the

Restarting treatment with Niaspan

IfyouhavenottakenNiaspanforsometimeandyouare

interestedinstartingitagain,consultthedoctorregardingthe

correct starting dose for you.

Switchingfromotherniacinpreparationstothis

medicine

Ifyouwishtoswitchfromanotherniacinpreparationtothis

medicine,consultthedoctorasitisnecessarytoadjustthe

dosage gradually.

Blood or urine tests

During treatment the doctor will conduct blood tests from

timetotime.Thisisinordertocheckyourliverfunction.

Youmustvisityourdoctorregularlyinordertomonitorthe

cholesterolandtriglyceridelevelsinyourbloodandtofollow

possible side effects.

If you have to undergo a test for certain hormones called

'catecholamines',tellthepersontakingthebloodorurine

thatyoutakeNiaspan.ThisisbecauseNiaspanmaymake

some tests less accurate.

Niaspan may also give false-positive results in urine sugar

test (Benedict's reagent).

Ifyouhaveanyfurtherquestionsregardinguseofthismedicine,

consult the doctor or pharmacist.

4.SIDE EFFECTS

Aswithallmedicines,useofNiaspancancausesideeffects

insomeusers.Donotbealarmedwhenreadingthelistofside

effects. You may not suffer from any of them.

StoptreatmentwithNiaspanandcontactthedoctor

immediately if an allergic reaction occurs.

Allergic(hypersensitivity)reactionsareveryrare,these

reactionsmayinclude:skinrash,hives(nettlerash),rashwith

blisters,swellingofthefaceorthroatwithdifficultyinbreathing,

shortness of breath, a drop in blood pressure or collapse.

Contactthedoctorimmediatelyifyouexperienceanyofthe

following side effects:

If you have pain, tenderness or weakness in the muscles,

especially if you are also taking statins.

Severe liver problem. The signs of a liver problem are:

increasedtiredness,darkurine,lossofappetite,palestools,

nausea,painintheupperabdomen,yellowingoftheskin

or the whites of the eyes, skin irritation.

Increased sugar (glucose) levels in the blood.

If you suffer from dizziness, inform the doctor.

Side effects that occur frequently

Flushing (see details further on in this leaflet)

Itching

Feeling warm

Tingling sensation

Rash

Diarrhea

Nausea

Vomiting

Abdominal pain and indigestion

Increased coughing

Flushingisaverycommonsideeffect.Itoccurswhenasmall

bloodvesselneartheskindilates(particularlyintheareaof

theface,neck,chestandback).Flushingmostlyoccurswhen

youstartusingNiaspanorwhenthedosageisincreased.It

islikelythatyouwillfeelanimprovementafterafewweeks

of treatment.

Thecharacteristicsymptomsofflushingare:asensationof

warmth, redness, tingling, itching.

Flushinggenerallyoccurs2-4hoursaftertakingNiaspanand

may continue for several hours.

Ifawakenedatnightbecauseofflushingorifyouwakeupfor

anotherreasonandfeelflushed,getupslowly,especiallyif

you also feel dizzy or faint, or if you take medicines to lower

blood pressure.

Takingaspirin(atadosageofupto325mg)about

30 minutes before taking Niaspan can minimize flushing.

Consult your doctor regarding this possibility.

Avoidinghotdrinks(includingcoffee),alcoholorspicyfoods

closetotakingthemedicine-canalsoreducethepossibility

of flushing.

Inrarecases,flushingmaybemoresevereandyoumayalso

feel dizzy, have a very fast or unusual heartbeat, shortness

ofbreath,sweating,chills,swelling(edema),andfainting.If

thishappens, stoptakingNiaspanandcontactadoctor

Side effects that occur infrequently

Headache, dizziness

Palpitations, rapid heartbeat

Shortness of breath

Sweating, dry skin, urticaria

Edema, pain, exhaustion, chills

Changes in blood tests indicating impairment of the body’s

functioning (e.g. liver, muscle, coagulation functions)

Side effects that occur rarely

Gout

Anorexia

Problems sleeping, nervousness

Migraines

Eye problems, blurred vision

Cardiac problems such as: atrial fibrillation, other

arrhythmias

Hypotension

Fainting

Flatulence (bloating) or belching, certain gastric or intestinal

problems (ulcers)

Jaundice

Darkening of the skin (hyperpigmentation) or patches of

darkened skin or skin discoloration

Muscle pain, muscle weakness, leg muscle cramps

Chest pain, face edema

Rhinitis – inflammation of the nose causing sneezing and

edematous nasal congestion, exhaustion, chills.

Ifanyofthesideeffectsbecomesseriousorifyouexperience

anysideeffectsnotmentionedinthisleaflet,consultthe

doctor.

5.HOW SHOULD THE MEDICINE BE STORED?

Avoidpoisoning!Thismedicineandallothermedicines

mustbestoredinasafeplaceoutofthereachofchildren

and/or infants to avoid poisoning.

Donotinducevomitingunlessexplicitlyinstructedtodo

so by the doctor.

Donottakemedicinesinthedark!Checkthelabelandthe

doseeachtimeyoutakeyourmedicine.Wearglassesifyou

need them.

Do not use the medicine after the expiry date (exp. date)

appearingonthepackage.Theexpirydatereferstothe

last day of that same month, if not noted otherwise.

Store below 25°C.

Keep the package tightly closed to protect from moisture.

6.FURTHER INFORMATION

In addition to the active ingredient the medicine also

contains -

Hypromellose,Povidone,StearicAcid,andthefollowing

coloringagents:FD&Cyellow#6/sunsetyellowFCF

AluminumLake,RedandYellowIronOxides,Polyethylene

Glycol, Hypromellose and Titanium Dioxide

How does the medicine look and what is the content of the

pack:

Niaspan is a film-coated, orange, medium-sized, unscored

tablet.

Niaspan500mg,750mgand1000mgtabletsareprovided

in bottles containing 30 or 90 tablets each.

Not all package sizes (30 or 90) are marketed.

Name of the manufacturer: Abbott Laboratories USA.

License holder and address: Abbott Medical Laboratories

Ltd., P.O.B. 58099, Tel-Aviv 61580.

This leaflet was checked and approved by the Ministry of

Health.

Registration number of the medicine in the National Drug

Registry of the Ministry of Health:

Niaspan 500 mg:148-45-33369-00

Niaspan 750 mg:148-46-33371-00

Niaspan 1000 mg:148-47-33373-00

DescriptionandCompositionoftheDrugProduct

NIASPAN500mg,750mg,1000mgExtendedReleaseFilmCoatedTablets

FULLPRESCRIBINGINFORMATION

1INDICATIONSANDUSAGE

Therapywithlipid-alteringagentsshouldbeonlyonecomponentofmultipleriskfactorinterventionin

individualsatsignificantlyincreasedriskforatheroscleroticvasculardiseaseduetohyperlipidemia.

Niacintherapyisindicatedasanadjuncttodietwhentheresponsetoadietrestrictedinsaturatedfat

andcholesterolandothernonpharmacologicmeasuresalonehasbeeninadequate.

1. NIASPANisindicatedtoreduceelevatedTC,LDL-C,ApoBandTGlevels,andto

increaseHDL-Cinpatientswithprimaryhyperlipidemiaandmixeddyslipidemia.

2. NIASPANincombinationwithsimvastatinorlovastatinisindicatedforthetreatmentof

primaryhyperlipidemiaandmixeddyslipidemiawhentreatmentwithNIASPAN,simvastatin,or

lovastatinmonotherapyisconsideredinadequate.

3. Inpatientswithahistoryofmyocardialinfarctionandhyperlipidemia,niacinisindicated

toreducetheriskofrecurrentnonfatalmyocardialinfarction.

4. Inpatientswithahistoryofcoronaryarterydisease(CAD)andhyperlipidemia,niacin,in

combinationwithabileacidbindingresin,isindicatedtoslowprogressionorpromote

regressionofatheroscleroticdisease.

5. NIASPANincombinationwithabileacidbindingresinisindicatedtoreduceelevated

TCandLDL-Clevelsinadultpatientswithprimaryhyperlipidemia.

LimitationsofUse

NoincrementalbenefitofNIASPANcoadministeredwithsimvastatinorlovastatinoncardiovascular

morbidityandmortalityoverandabovethatdemonstratedforniacin,simvastatin,orlovastatin

monotherapyhasbeenestablished..

2DOSAGEANDADMINISTRATION

NIASPANshouldbetakenatbedtime,afteralow-fatsnack,anddosesshouldbeindividualized

accordingtopatientresponse.TherapywithNIASPANmustbeinitiatedat500mgatbedtimeinorder

toreducetheincidenceandseverityofsideeffectswhichmayoccurduringearlytherapy.The

recommendeddoseescalationisshowninTable1below.

Table 1. Recommended Dosing

Week(s) Dailydose NIASPANDosage

INITIAL

TITRATION 1to4 500mg

1NIASPAN500mgtabletatbedtime

SCHEDULE 5to8 1000mg

1NIASPAN1000mgtabletor

2NIASPAN500mgtabletsatbedtime

* 1500mg

2NIASPAN750mgtabletsor

3NIASPAN500mgtabletsatbedtime

* 2000mg

2NIASPAN1000mgtabletsor

4NIASPAN500mgtabletsatbedtime

*AfterWeek8,titratetopatientresponseandtolerance.Ifresponseto1000mgdailyis

inadequate,increasedoseto1500mgdaily;maysubsequentlyincreasedoseto2000

mgdaily.Dailydoseshouldnotbeincreasedmorethan500mgina4-weekperiod,and

dosesabove2000mgdailyarenotrecommended.Womenmayrespondatlowerdoses

thanmen.

MaintenanceDose

ThedailydosageofNIASPANshouldnotbeincreasedbymorethan500mginany4–weekperiod.

Therecommendedmaintenancedoseis1000mg(two500mgtabletsorone1000mgtablet)to2000

mg(two1000mgtabletsorfour500mgtablets)oncedailyatbedtime.Dosesgreaterthan2000mg

dailyarenotrecommended.WomenmayrespondatlowerNIASPANdosesthanmen [seeClinical

Studies(14.2)].

Single-dosebioavailabilitystudieshavedemonstratedthattwoofthe500mgandoneofthe1000mg

tabletstrengthsareinterchangeablebutthreeofthe500mgandtwoofthe750mgtabletstrengths

arenotinterchangeable.

IflipidresponsetoNIASPANaloneisinsufficientorifhigherdosesofNIASPANarenotwell

tolerated,somepatientsmaybenefitfromcombinationtherapywithabileacidbindingresinorstatin

[seeDrugInteractions(7.3),ConcomitantTherapybelowandClinicalStudies(14.3,14.4)].

Flushingoftheskin [seeAdverseReactions(6.1)]maybereducedinfrequencyorseverityby

pretreatmentwithaspirin(uptotherecommendeddoseof325mgtaken30minutespriorto

NIASPANdose).Tolerancetothisflushingdevelopsrapidlyoverthecourseofseveralweeks.

Flushing,pruritus,andgastrointestinaldistressarealsogreatlyreducedbyslowlyincreasingthedose

ofniacinandavoidingadministrationonanemptystomach.Concomitantalcoholic,hotdrinksorspicy

foodsmayincreasethesideeffectsofflushingandpruritusandshouldbeavoidedaroundthetimeof

NIASPANingestion.

EquivalentdosesofNIASPANshouldnotbesubstitutedforsustained-release(modified-release,

timed-release)niacinpreparationsorimmediate-release(crystalline)niacin [seeWarningsand

Precautions(5)].Patientspreviouslyreceivingotherniacinproductsshouldbestartedwiththe

recommendedNIASPANtitrationschedule(seeTable1),andthedoseshouldsubsequentlybe

individualizedbasedonpatientresponse.

IfNIASPANtherapyisdiscontinuedforanextendedperiod,reinstitutionoftherapyshouldincludea

titrationphase(seeTable1).

NIASPANtabletsshouldbetakenwholeandshouldnotbebroken,crushedorchewedbefore

swallowing.

ConcomitantTherapy

ConcomitantTherapywithLovastatinorSimvastatin

PatientsalreadyreceivingastabledoseoflovastatinorsimvastatinwhorequirefurtherTG-lowering

orHDL-raising(e.g.,toachieveNCEPnon-HDL-Cgoals),mayreceiveconcomitantdosagetitration

withNIASPANperNIASPANrecommendedinitialtitrationschedule [seeDosageandAdministration

(2)].ForpatientsalreadyreceivingastabledoseofNIASPANwhorequirefurtherLDL-lowering(e.g.,

toachieveNCEPLDL-Cgoals),theusualrecommendedstartingdoseoflovastatinandsimvastatinis

20mgonceaday.Doseadjustmentsshouldbemadeatintervalsof4weeksormore.Combination

therapywithNIASPANandlovastatinorNIASPANandsimvastatinshouldnotexceeddosesof2000

mgNIASPANand40mglovastatinorsimvastatindaily.

DosageinPatientswithRenalorHepaticImpairment

UseofNIASPANinpatientswithrenalorhepaticimpairmenthasnotbeenstudied.NIASPANis

contraindicatedinpatientswithsignificantorunexplainedhepaticdysfunction.NIASPANshouldbe

usedwithcautioninpatientswithrenalimpairment [seeWarningsandPrecautions(5)].

3DOSAGEFORMSANDSTRENGTHS

500mgunscored,medium-orange,film-coated,capsule-shapedtablets

750mgunscored,medium-orange,film-coated,capsule-shapedtablets

1000mgunscored,medium-orange,film-coated,capsule-shapedtablets

4CONTRAINDICATIONS

NIASPANiscontraindicatedinthefollowingconditions:

Activeliverdiseaseorunexplainedpersistentelevationsinhepatictransaminases [see

WarningsandPrecautions(5.2)]

Patientswithactivepepticulcerdisease

Patientswitharterialbleeding

Hypersensitivitytoniacinoranycomponentofthismedication [seeAdverseReactions

(6.1)]

5WARNINGSANDPRECAUTIONS

NIASPANpreparationsshouldnotbesubstitutedforequivalentdosesofimmediate-release

(crystalline)niacin.Forpatientsswitchingfromimmediate-releaseniacintoNIASPAN,therapywith

NIASPANshouldbeinitiatedwithlowdoses(i.e.,500mgatbedtime)andtheNIASPANdoseshould

thenbetitratedtothedesiredtherapeuticresponse [seeDosageandAdministration(2)].

CautionshouldalsobeusedwhenNIASPANisusedinpatientswithunstableanginaorintheacute

phaseofanMI,particularlywhensuchpatientsarealsoreceivingvasoactivedrugssuchasnitrates,

calciumchannelblockers,oradrenergicblockingagents.

Niacinisrapidlymetabolizedbytheliver,andexcretedthroughthekidneys.NIASPANis

contraindicatedinpatientswithsignificantorunexplainedhepaticimpairment [seeContraindications

(4)andWarningsandPrecautions(5.2)]andshouldbeusedwithcautioninpatientswithrenal

impairment.Patientswithapasthistoryofjaundice,hepatobiliarydisease,orpepticulcershouldbe

observedcloselyduringNIASPANtherapy.

5.1SkeletalMuscle

Casesofrhabdomyolysishavebeenassociatedwithconcomitantadministrationoflipid-altering

doses(≥1g/day)ofniacinandstatins.Physicianscontemplatingcombinedtherapywithstatinsand

NIASPANshouldcarefullyweighthepotentialbenefitsandrisksandshouldcarefullymonitorpatients

foranysignsandsymptomsofmusclepain,tenderness,orweakness,particularlyduringtheinitial

monthsoftherapyandduringanyperiodsofupwarddosagetitrationofeitherdrug.Periodicserum

creatinephosphokinase(CPK)andpotassiumdeterminationsshouldbeconsideredinsuch

situations,butthereisnoassurancethatsuchmonitoringwillpreventtheoccurrenceofsevere

myopathy.

Theriskformyopathyandrhabdomyolysisareincreasedwhenlovastatinorsimvastatinare

coadministeredwithNIASPAN,particularlyinelderlypatientsandpatientswithdiabetes,renalfailure,

oruncontrolledhypothyroidism.

5.2LiverDysfunction

Casesofseverehepatictoxicity,includingfulminanthepaticnecrosis,haveoccurredinpatientswho

havesubstitutedsustained-release(modified-release,timed-release)niacinproductsforimmediate-

release(crystalline)niacinatequivalentdoses.

NIASPANshouldbeusedwithcautioninpatientswhoconsumesubstantialquantitiesofalcohol

and/orhaveapasthistoryofliverdisease.Activeliverdiseasesorunexplainedtransaminase

elevationsarecontraindicationstotheuseofNIASPAN.

Niacinpreparationshavebeenassociatedwithabnormallivertests.Inthreeplacebo-controlled

clinicaltrialsinvolvingtitrationtofinaldailyNIASPANdosesrangingfrom500to3000mg,245

patientsreceivedNIASPANforameandurationof17weeks.Nopatientwithnormalserum

transaminaselevels(AST,ALT)atbaselineexperiencedelevationstomorethan3timestheupper

limitofnormal(ULN)duringtreatmentwithNIASPAN.Inthesestudies,fewerthan1%(2/245)of

NIASPANpatientsdiscontinuedduetotransaminaseelevationsgreaterthan2timestheULN.

InthreesafetyandefficacystudieswithacombinationtabletofNIASPANandlovastatininvolving

titrationtofinaldailydoses(expressedasmgofniacin/mgoflovastatin)500mg/10mgto2500

mg/40mg,tenof1028patients(1.0%)experiencedreversibleelevationsinAST/ALTtomorethan3

timestheULN.Threeoftenelevationsoccurredatdosesoutsidetherecommendeddosinglimitof

2000mg/40mg;nopatientreceiving1000mg/20mghad3-foldelevationsinAST/ALT.

Niacinextended-releaseandsimvastatincancauseabnormallivertests.Inasimvastatin-controlled,

24weekstudywithafixeddosecombinationofNIASPANandsimvastatinin641patients,therewere

nopersistentincreases(morethan3xtheULN)inserumtransaminases.Inthreeplacebo-controlled

clinicalstudiesofextended-releaseniacintherewerenopatientswithnormalserumtransaminase

levelsatbaselinewhoexperiencedelevationstomorethan3xtheULN.Persistentincreases(more

than3xtheULN)inserumtransaminaseshaveoccurredinapproximately1%ofpatientswho

receivedsimvastatininclinicalstudies.Whendrugtreatmentwasinterruptedordiscontinuedinthese

patients,thetransaminaseslevelsusuallyfellslowlytopretreatmentlevels.Theincreaseswerenot

associatedwithjaundiceorotherclinicalsignsorsymptoms.Therewasnoevidenceof

hypersensitivity.

Intheplacebo-controlledclinicaltrialsandthelong-termextensionstudy,elevationsintransaminases

didnotappeartoberelatedtotreatmentduration;elevationsinASTlevelsdidappeartobedose

related.TransaminaseelevationswerereversibleupondiscontinuationofNIASPAN.

LiverfunctiontestsshouldbeperformedonallpatientsduringtherapywithNIASPAN.Serum

transaminaselevels,includingASTandALT(SGOTandSGPT),shouldbemonitoredbefore

treatmentbegins,every6to12weeksforthefirstyear,andperiodicallythereafter(e.g.,at

approximately6-monthintervals).Specialattentionshouldbepaidtopatientswhodevelopelevated

serumtransaminaselevels,andinthesepatients,measurementsshouldberepeatedpromptlyand

thenperformedmorefrequently.Ifthetransaminaselevelsshowevidenceofprogression,particularly

iftheyriseto3timesULNandarepersistent,oriftheyareassociatedwithsymptomsofnausea,

fever,and/ormalaise,thedrugshouldbediscontinued.

5.3LaboratoryAbnormalities

IncreaseinBloodGlucose:Niacintreatmentcanincreasefastingbloodglucose.Frequentmonitoring

ofbloodglucoseshouldbeperformedtoascertainthatthedrugisproducingnoadverseeffects.

Diabeticpatientsmayexperienceadose-relatedincreaseinglucoseintolerance.Diabeticor

potentiallydiabeticpatientsshouldbeobservedcloselyduringtreatmentwithNIASPAN,particularly

duringthefirstfewmonthsofuseordoseadjustment;adjustmentofdietand/orhypoglycemic

therapymaybenecessary.

Reductioninplateletcount:NIASPANhasbeenassociatedwithsmallbutstatisticallysignificant

dose-relatedreductionsinplateletcount(meanof-11%with2000mg).Cautionshouldbeobserved

whenNIASPANisadministeredconcomitantlywithanticoagulants;plateletcountsshouldbe

monitoredcloselyinsuchpatients.

IncreaseinProthrombinTime(PT):NIASPANhasbeenassociatedwithsmallbutstatistically

significantincreasesinprothrombintime(meanofapproximately+4%);accordingly,patients

undergoingsurgeryshouldbecarefullyevaluated.CautionshouldbeobservedwhenNIASPANis

administeredconcomitantlywithanticoagulants;prothrombintimeshouldbemonitoredcloselyin

suchpatients.

IncreaseinUricAcid:Elevateduricacidlevelshaveoccurredwithniacintherapy,thereforeusewith

cautioninpatientspredisposedtogout.

DecreaseinPhosphorus:Inplacebo-controlledtrials,NIASPANhasbeenassociatedwithsmallbut

statisticallysignificant,dose-relatedreductionsinphosphoruslevels(meanof-13%with2000mg).

Althoughthesereductionsweretransient,phosphoruslevelsshouldbemonitoredperiodicallyin

patientsatriskforhypophosphatemia.

6ADVERSEREACTIONS

Becauseclinicalstudiesareconductedunderwidelyvaryingconditions,adversereactionrates

observedintheclinicalstudiesofadrugcannotbedirectlycomparedtoratesintheclinicalstudiesof

anotherdrugandmaynotreflecttheratesobservedinpractice.

6.1ClinicalStudiesExperience

Intheplacebo-controlledclinicaltrialsdatabaseof402patients(agerange21-75years,33%women,

89%Caucasians,7%Blacks,3%Hispanics,1%Asians)withamediantreatmentdurationof16

weeks,16%ofpatientsonNIASPANand4%ofpatientsonplacebodiscontinuedduetoadverse

reactions.ThemostcommonadversereactionsinthegroupofpatientstreatedwithNIASPANthat

ledtotreatmentdiscontinuationandoccurredatarategreaterthanplacebowereflushing(6%vs.

0%),rash(2%vs.0%),diarrhea(2%vs.0%),nausea(1%vs.0%),andvomiting(1%vs.0%).The

mostcommonlyreportedadversereactions(incidence>5%andgreaterthanplacebo)inthe

NIASPANcontrolledclinicaltrialdatabaseof402patientswereflushing,diarrhea,nausea,vomiting,

increasedcoughandpruritus.

Intheplacebo-controlledclinicaltrials,flushingepisodes(i.e.,warmth,redness,itchingand/or

tingling)werethemostcommontreatment-emergentadversereactions(reportedbyasmanyas88%

ofpatients)forNIASPAN.Spontaneousreportssuggestthatflushingmayalsobeaccompaniedby

symptomsofdizziness,tachycardia,palpitations,shortnessofbreath,sweating,burning

sensation/skinburningsensation,chills,and/oredema,whichinrarecasesmayleadtosyncope.In

pivotalstudies,6%(14/245)ofNIASPANpatientsdiscontinuedduetoflushing.Incomparisonsof

immediate-release(IR)niacinandNIASPAN,althoughtheproportionofpatientswhoflushedwas

similar,fewerflushingepisodeswerereportedbypatientswhoreceivedNIASPAN.Following4

weeksofmaintenancetherapyatdailydosesof1500mg,theincidenceofflushingoverthe4-week

periodaveraged8.6eventsperpatientforIRniacinversus1.9followingNIASPAN.

Otheradversereactionsoccurringin≥5%ofpatientstreatedwithNIASPANandatanincidence

greaterthanplaceboareshowninTable2below.

Table 2. Treatment-Emergent Adverse Reactions by Dose Levelin≥5%of

Patients andat an Incidence Greater than Placebo; Regardless of Causality

Assessment in Placebo-Controlled Clinical Trials

Placebo-ControlledStudies

NIASPANTreatment @

RecommendedDaily

MaintenanceDoses

Placebo500mg ‡ 1000mg1500mg2000mg

(n=157)(n=87)(n=110)(n=136)(n=95)

% % % % %

GastrointestinalDisorders

Diarrhea 13 7 10 10 14

Nausea 7 5 6 4 11

Vomiting 4 0 2 4 9

Respiratory

Cough,Increased 6 3 2 <2 8

SkinandSubcutaneousTissue

Disorders

Pruritus 2 8 0 3 0

Rash 0 5 5 5 0

VascularDisorders

Flushing & 19 68 69 63 55

Note:Percentagesarecalculatedfromthetotalnumberofpatientsineachcolumn.

Adversereactionsarereportedattheinitialdosewheretheyoccur.

Pooledresultsfromplacebo-controlledstudies;forNIASPAN,n=245andmedian

treatmentduration=16weeks.NumberofNIASPANpatients(n)arenotadditiveacross

doses.

The500mg/daydoseisoutsidetherecommendeddailymaintenancedosingrange

[seeDosageandAdministration(2)].

& 10patientsdiscontinuedbeforereceiving500mg,thereforetheywerenotincluded.

Ingeneral,theincidenceofadverseeventswashigherinwomencomparedtomen.

6.2PostmarketingExperience

Becausethebelowreactionsarereportedvoluntarilyfromapopulationofuncertainsize,itis

generallynotpossibletoreliablyestimatetheirfrequencyorestablishacausalrelationshiptodrug

exposure.

Thefollowingadditionaladversereactionshavebeenidentifiedduringpost-approvaluseof

NIASPAN:

Hypersensitivityreactions,includinganaphylaxis,angioedema,urticaria,flushing,dyspnea,tongue

edema,larynxedema,faceedema,peripheraledema,laryngismus,andvesiculobullousrash;

maculopapularrash;dryskin;tachycardia;palpitations;atrialfibrillation;othercardiacarrhythmias;

syncope;hypotension;posturalhypotension;blurredvision;macularedema;pepticulcers;eructation;

flatulence;hepatitis;jaundice;decreasedglucosetolerance;gout;myalgia;myopathy;dizziness;

insomnia;asthenia;nervousness;paresthesia;dyspnea;sweating;burningsensation/skinburning

sensation;skindiscoloration,andmigraine.

ClinicalLaboratoryAbnormalities

Chemistry:Elevationsinserumtransaminases [seeWarningsandPrecautions(5.2)],LDH,fasting

glucose,uricacid,totalbilirubin,amylaseandcreatinekinase,andreductioninphosphorus.

Hematology:Slightreductionsinplateletcountsandprolongationinprothrombintime [seeWarnings

andPrecautions(5.3)].

7DRUGINTERACTIONS

7.1Statins

Cautionshouldbeusedwhenprescribingniacin(≥1gm/day)withstatinsasthesedrugscanincrease

riskofmyopathy/rhabdomyolysis.CombinationtherapywithNIASPANandlovastatinorNIASPAN

andsimvastatinshouldnotexceeddosesof2000mgNIASPANand40mglovastatinorsimvastatin

daily. [seeWarningsandPrecautions(5)andClinicalPharmacology(12.3)].

7.2BileAcidSequestrants

An invitrostudyresultssuggestthatthebileacid-bindingresinshavehighniacinbindingcapacity.

Therefore,4to6hours,orasgreatanintervalaspossible,shouldelapsebetweentheingestionof

bileacid-bindingresinsandtheadministrationofNIASPAN [seeClinicalPharmacology(12.3)].

7.3Aspirin

Concomitantaspirinmaydecreasethemetabolicclearanceofnicotinicacid.Theclinicalrelevanceof

thisfindingisunclear.

7.4AntihypertensiveTherapy

Niacinmaypotentiatetheeffectsofganglionicblockingagentsandvasoactivedrugsresultingin

posturalhypotension.

7.5Other

Vitaminsorothernutritionalsupplementscontaininglargedosesofniacinorrelatedcompoundssuch

asnicotinamidemaypotentiatetheadverseeffectsofNIASPAN.

7.6LaboratoryTestInteractions

Niacinmayproducefalseelevationsinsomefluorometricdeterminationsofplasmaorurinary

catecholamines.Niacinmayalsogivefalse-positivereactionswithcupricsulfatesolution(Benedict’s

reagent)inurineglucosetests.

8USEINSPECIFICPOPULATIONS

8.1Pregnancy

PregnancyCategoryC.

AnimalreproductionstudieshavenotbeenconductedwithniacinorwithNIASPAN.Itisalsonot

knownwhetherniacinatdosestypicallyusedforlipiddisorderscancausefetalharmwhen

administeredtopregnantwomenorwhetheritcanaffectreproductivecapacity.Ifawomanreceiving

niacinforprimaryhyperlipidemiabecomespregnant,thedrugshouldbediscontinued.Ifawoman

beingtreatedwithniacinforhypertriglyceridemiaconceives,thebenefitsandrisksofcontinued

therapyshouldbeassessedonanindividualbasis.

Allstatinsarecontraindicatedinpregnantandnursingwomen.WhenNIASPANisadministeredwith

astatininawomanofchildbearingpotential,refertothepregnancycategoryandproductlabelingfor

thestatin.

8.3NursingMothers

Niacinisexcretedintohumanmilkbuttheactualinfantdoseorinfantdoseasapercentofthe

maternaldoseisnotknown.Becauseofthepotentialforseriousadversereactionsinnursinginfants

fromlipid-alteringdosesofnicotinicacid,adecisionshouldbemadewhethertodiscontinuenursing

ortodiscontinuethedrug,takingintoaccounttheimportanceofthedrugtothemother.Nostudies

havebeenconductedwithNIASPANinnursingmothers.

8.4PediatricUse

Safetyandeffectivenessofniacintherapyinpediatricpatients(≤16years)havenotbeenestablished.

8.5GeriatricUse

Of979patientsinclinicalstudiesofNIASPAN,21%ofthepatientswereage65andover.Nooverall

differencesinsafetyandeffectivenesswereobservedbetweenthesepatientsandyoungerpatients,

andotherreportedclinicalexperiencehasnotidentifieddifferencesinresponsesbetweentheelderly

andyoungerpatients,butgreatersensitivityofsomeolderindividualscannotberuledout.

8.6RenalImpairment

Nostudieshavebeenperformedinthispopulation.NIASPANshouldbeusedwithcautioninpatients

withrenalimpairment [seeWarningsandPrecautions(5)].

8.7HepaticImpairment

Nostudieshavebeenperformedinthispopulation.NIASPANshouldbeusedwithcautioninpatients

withapasthistoryofliverdiseaseand/orwhoconsumesubstantialquantitiesofalcohol.Activeliver

disease,unexplainedtransaminaseelevationsandsignificantorunexplainedhepaticdysfunctionare

contraindicationstotheuseofNIASPAN [seeContraindications(4.0)andWarningsandPrecautions

(5.2)].

8.8Gender

Datafromtheclinicaltrialssuggestthatwomenhaveagreaterhypolipidemicresponsethanmenat

equivalentdosesofNIASPAN.

10OVERDOSAGE

Supportivemeasuresshouldbeundertakenintheeventofanoverdose.

11DESCRIPTION

NIASPAN(niacintablet,film-coatedextended-release),containsniacin,whichattherapeuticdosesis

anantihyperlipidemicagent.Niacin(nicotinicacid,or3-pyridinecarboxylicacid)isawhite,crystalline

powder,verysolubleinwater,withthefollowingstructuralformula:

NIASPANisanunscored,medium-orange,film-coatedtabletfororaladministrationandisavailable

inthreetabletstrengthscontaining500,750,and1000mgniacin.NIASPANtabletsalsocontainthe

inactiveingredientshypromellose,povidone,stearicacid,andthefollowingcoloringagents:FD&C

yellow#6/sunsetyellowFCFAluminumLake,redandyellowironoxides,polyethyleneglycoland

titaniumdioxide.

12CLINICALPHARMACOLOGY

12.1MechanismofAction

Themechanismbywhichniacinalterslipidprofileshasnotbeenwelldefined.Itmayinvolveseveral

actionsincludingpartialinhibitionofreleaseoffreefattyacidsfromadiposetissue,andincreased

lipoproteinlipaseactivity,whichmayincreasetherateofchylomicrontriglycerideremovalfrom

plasma.NiacindecreasestherateofhepaticsynthesisofVLDLandLDL,anddoesnotappearto

affectfecalexcretionoffats,sterols,orbileacids.

12.2Pharmacodynamics

Niacinfunctionsinthebodyafterconversiontonicotinamideadeninedinucleotide(NAD)intheNAD

coenzymesystem.Niacin(butnotnicotinamide)ingramdosesreducestotalcholesterol(TC),low

densitylipoproteincholesterol(LDL-C),andtriglycerides(TG),andincreaseshigh-densitylipoprotein

cholesterol(HDL-C).Themagnitudeofindividuallipidandlipoproteinresponsesmaybeinfluenced

bytheseverityandtypeofunderlyinglipidabnormality.TheincreaseinHDL-Cisassociatedwithan

increaseinapolipoproteinA-I(ApoA-I)andashiftinthedistributionofHDLsubfractions.Theseshifts

includeanincreaseintheHDL

:HDL

ratio,andanelevationinlipoproteinA-I(LpA-I,anHDL-C

particlecontainingonlyApoA-I).NiacintreatmentalsodecreasesserumlevelsofapolipoproteinB-

100(ApoB),themajorproteincomponentoftheverylow-densitylipoprotein(VLDL)andLDL

fractions,andofLp(a),avariantformofLDLindependentlyassociatedwithcoronaryrisk.Inaddition,

preliminaryreportssuggestthatniacincausesfavorableLDLparticlesizetransformations,although

theclinicalrelevanceofthiseffectrequiresfurtherinvestigation.Theeffectofniacin-inducedchanges

inlipids/proteinsoncardiovascularmorbidityormortalityinindividualswithoutpreexistingcoronary

diseasehasnotbeenestablished.

AvarietyofclinicalstudieshavedemonstratedthatelevatedlevelsofTC,LDL-C,andApoBpromote

humanatherosclerosis.Similarly,decreasedlevelsofHDL-Careassociatedwiththedevelopmentof

atherosclerosis.Epidemiologicalinvestigationshaveestablishedthatcardiovascularmorbidityand

mortalityvarydirectlywiththelevelofTotal-CandLDL-C,andinverselywiththelevelofHDL-C.

LikeLDL,cholesterol-enrichedtriglyceride-richlipoproteins,includingVLDL,intermediate-density

lipoprotein(IDL),andtheirremnants,canalsopromoteatherosclerosis.ElevatedplasmaTGare

frequentlyfoundinatriadwithlowHDL-ClevelsandsmallLDLparticles,aswellasinassociation

withnon-lipidmetabolicriskfactorsforcoronaryheartdisease(CHD).Assuch,totalplasmaTGhas

notconsistentlybeenshowntobeanindependentriskfactorforCHD.Furthermore,theindependent

effectofraisingHDL-CorloweringTGontheriskofcoronaryandcardiovascularmorbidityand

mortalityhasnotbeendetermined.

12.3Pharmacokinetics

Absorption

Duetoextensiveandsaturablefirst-passmetabolism,niacinconcentrationsinthegeneralcirculation

aredosedependentandhighlyvariable.Timetoreachthemaximumniacinplasmaconcentrations

wasabout5hoursfollowingNIASPAN.Toreducetheriskofgastrointestinal(GI)upset,

administrationofNIASPANwithalow-fatmealorsnackisrecommended.

Single-dosebioavailabilitystudieshavedemonstratedthatthe500mgand1000mgtabletstrengths

aredosageformequivalentbutthe500mgand750mgtabletstrengthsarenotdosageform

equivalent.

Metabolism

Thepharmacokineticprofileofniaciniscomplicatedduetoextensivefirst-passmetabolismthatis

dose-ratespecificand,atthedosesusedtotreatdyslipidemia,saturable.Inhumans,onepathwayis

throughasimpleconjugationstepwithglycinetoformnicotinuricacid(NUA).NUAisthenexcretedin

theurine,althoughtheremaybeasmallamountofreversiblemetabolismbacktoniacin.Theother

pathwayresultsintheformationofnicotinamideadeninedinucleotide(NAD).Itisunclearwhether

nicotinamideisformedasaprecursorto,orfollowingthesynthesisof,NAD.Nicotinamideisfurther

metabolizedtoatleastN-methylnicotinamide(MNA)andnicotinamide-N-oxide(NNO).MNAisfurther

metabolizedtotwoothercompounds,N-methyl-2-pyridone-5-carboxamide(2PY)andN-methyl-4-

pyridone-5-carboxamide(4PY).Theformationof2PYappearstopredominateover4PYinhumans.

Atthedosesusedtotreathyperlipidemia,thesemetabolicpathwaysaresaturable,whichexplains

thenonlinearrelationshipbetweenniacindoseandplasmaconcentrationsfollowingmultiple-dose

NIASPANadministration.

Nicotinamidedoesnothavehypolipidemicactivity;theactivityoftheothermetabolitesisunknown.

Elimination

Followingsingleandmultipledoses,approximately60to76%oftheniacindoseadministeredas

NIASPANwasrecoveredinurineasniacinandmetabolites;upto12%wasrecoveredasunchanged

niacinaftermultipledosing.Theratioofmetabolitesrecoveredintheurinewasdependentonthe

doseadministered.

PediatricUse

Nopharmacokineticstudieshavebeenperformedinthispopulation(≤16years) [seeUseinSpecific

Populations(8.4)].

GeriatricUse

Nopharmacokineticstudieshavebeenperformedinthispopulation(>65years) [seeUseinSpecific

Populations(8.5)].

RenalImpairment

Nopharmacokineticstudieshavebeenperformedinthispopulation.NIASPANshouldbeusedwith

cautioninpatientswithrenaldisease [seeWarningsandPrecautions(5)].

HepaticImpairment

Nopharmacokineticstudieshavebeenperformedinthispopulation.Activeliverdisease,unexplained

transaminaseelevationsandsignificantorunexplainedhepaticdysfunctionarecontraindicationsto

theuseofNIASPAN [seeContraindications(4)andWarningsandPrecautions(5.2)].

Gender

Steady-stateplasmaconcentrationsofniacinandmetabolitesafteradministrationofNIASPANare

generallyhigherinwomenthaninmen,withthemagnitudeofthedifferencevaryingwithdoseand

metabolite.Thisgenderdifferencesobservedinplasmalevelsofniacinanditsmetabolitesmaybe

duetogender-specificdifferencesinmetabolicrateorvolumeofdistribution.Recoveryofniacinand

metabolitesinurine,however,isgenerallysimilarformenandwomen,indicatingthatabsorptionis

similarforbothgenders [seeGender(8.8)].

Druginteractions

Fluvastatin

Niacindidnotaffectfluvastatinpharmacokinetics [seeDrugInteractions(7.1)].

Lovastatin

WhenNIASPAN2000mgandlovastatin40mgwereco-administered,NIASPANincreasedlovastatin

andAUCby2%and14%,respectively,anddecreasedlovastatinacidC

andAUCby22%

and2%,respectively.LovastatinreducedNIASPANbioavailabilityby2-3% [seeDrugInteractions

(7.1)].

Simvastatin

WhenNIASPAN2000mgandsimvastatin40mgwereco-administered,NIASPANincreased

simvastatinC

andAUCby1%and9%,respectively,andsimvastatinacidC

andAUCby2%

and18%,respectively.SimvastatinreducedNIASPANbioavailabilityby2% [seeDrugInteractions

(7.1)].

BileAcidSequestrants

An invitrostudywascarriedoutinvestigatingtheniacin-bindingcapacityofcolestipoland

cholestyramine.About98%ofavailableniacinwasboundtocolestipol,with10to30%bindingto

cholestyramine [seeDrugInteractions(7.2)].

13NONCLINICALTOXICOLOGY

13.1CarcinogenesisandMutagenesisandImpairmentofFertility

Niacinadministeredtomiceforalifetimeasa1%solutionindrinkingwaterwasnotcarcinogenic.

Themiceinthisstudyreceivedapproximately6to8timesahumandoseof3000mg/dayas

determinedonamg/m 2 basis.NiacinwasnegativeformutagenicityintheAmestest.Nostudieson

impairmentoffertilityhavebeenperformed.NostudieshavebeenconductedwithNIASPAN

regardingcarcinogenesis,mutagenesis,orimpairmentoffertility.

14CLINICALSTUDIES

14.1NiacinClinicalStudies

TheroleofLDL-Cinatherogenesisissupportedbypathologicalobservations,clinicalstudies,and

manyanimalexperiments.Observationalepidemiologicalstudieshaveclearlyestablishedthathigh

TCorLDL-CandlowHDL-CareriskfactorsforCHD.Additionally,elevatedlevelsofLp(a)havebeen

showntobeindependentlyassociatedwithCHDrisk.

Niacin’sabilitytoreducemortalityandtheriskofdefinite,nonfatalmyocardialinfarction(MI)hasbeen

assessedinlong-termstudies.TheCoronaryDrugProject,completedin1975,wasdesignedto

assessthesafetyandefficacyofniacinandotherlipid-alteringdrugsinmen30to64yearsoldwitha

historyofMI.Overanobservationperiodof5years,niacintreatmentwasassociatedwitha

statisticallysignificantreductioninnonfatal,recurrentMI.Theincidenceofdefinite,nonfatalMIwas

8.9%forthe1,119patientsrandomizedtonicotinicacidversus12.2%forthe2,789patientswho

receivedplacebo( p<0.004).Totalmortalitywassimilarinthetwogroupsat5years(24.4%with

nicotinicacidversus25.4%withplacebo; p=N.S.).Atthetimeofa15-yearfollow-up,therewere11%

(69)fewerdeathsintheniacingroupcomparedtotheplacebocohort(52.0%versus58.2%;

p=0.0004).However,mortalityat15yearswasnotanoriginalendpointoftheCoronaryDrugProject.

Inaddition,patientshadnotreceivedniacinforapproximately9years,andconfoundingvariables

suchasconcomitantmedicationuseandmedicalorsurgicaltreatmentswerenotcontrolled.

TheCholesterol-LoweringAtherosclerosisStudy(CLAS)wasarandomized,placebo-controlled,

angiographictrialtestingcombinedcolestipolandniacintherapyin162non-smokingmaleswith

previouscoronarybypasssurgery.Theprimary,per-subjectcardiacendpointwasglobalcoronary

arterychangescore.After2years,61%ofpatientsintheplacebocohortshoweddisease

progressionbyglobalchangescore(n=82),comparedwithonly38.8%ofdrug-treatedsubjects

(n=80),whenbothnativearteriesandgraftswereconsidered( p<0.005);diseaseregressionalso

occurredmorefrequentlyinthedrug-treatedgroup(16.2%versus2.4%; p=0.002).Inafollow-upto

thistrialinasubgroupof103patientstreatedfor4years,again,significantlyfewerpatientsinthe

drug-treatedgroupdemonstratedprogressionthanintheplacebocohort(48%versus85%,

respectively; p<0.0001).

TheFamilialAtherosclerosisTreatmentStudy(FATS)in146menages62andyoungerwithApoB

levels≥125mg/dL,establishedcoronaryarterydisease,andfamilyhistoriesofvasculardisease,

assessedchangeinseverityofdiseaseintheproximalcoronaryarteriesbyquantitative

arteriography.Patientsweregivendietarycounselingandrandomizedtotreatmentwitheither

conventionaltherapywithdoubleplacebo(orplacebopluscolestipoliftheLDL-Cwaselevated);

lovastatinpluscolestipol;orniacinpluscolestipol.Intheconventionaltherapygroup,46%ofpatients

haddiseaseprogression(andnoregression)inatleastoneofnineproximalcoronarysegments;

regressionwastheonlychangein11%.Incontrast,progression(astheonlychange)wasseenin

only25%intheniacinpluscolestipolgroup,whileregressionwasobservedin39%.Thoughnotan

originalendpointofthetrial,clinicalevents(death,MI,orrevascularizationforworseningangina)

occurredin10of52patientswhoreceivedconventionaltherapy,comparedwith2of48whoreceived

niacinpluscolestipol.

TheHarvardAtherosclerosisReversibilityProject(HARP)wasarandomizedplacebo-controlled,2.5-

yearstudyoftheeffectofastepped-careantihyperlipidemicdrugregimenon91patients(80men

and11women)withCHDandaveragebaselineTClevelslessthan250mg/dLandratiosofTCto

HDL-Cgreaterthan4.0.DrugtreatmentconsistedofanHMG-CoAreductaseinhibitoradministered

aloneasinitialtherapyfollowedbyadditionofvaryingdosagesofeitheraslow-releasenicotinicacid,

cholestyramine,orgemfibrozil.AdditionofnicotinicacidtotheHMG-CoAreductaseinhibitorresulted

infurtherstatisticallysignificantmeanreductionsinTC,LDL-C,andTG,aswellasafurtherincrease

inHDL-Cinamajorityofpatients(40of44patients).TheratiosofTCtoHDL-CandLDL-CtoHDL-C

werealsosignificantlyreducedbythiscombinationdrugregimen [seeWarningsandPrecautions

(5.1)].

14.2NIASPANClinicalStudies

Placebo-ControlledClinicalStudiesinPatientswithPrimaryHyperlipidemiaandMixedDyslipidemia:

Intworandomized,double-blind,parallel,multi-center,placebo-controlledtrials,NIASPANdosedat

1000,1500or2000mgdailyatbedtimewithalow-fatsnackfor16weeks(including4weeksofdose

escalation)favorablyalteredlipidprofilescomparedtoplacebo(Table3).Womenappearedtohavea

greaterresponsethanmenateachNIASPANdoselevel(see GenderEffect,below).

Table 3. Lipid Response to NIASPANTherapy

MeanPercentChangefromBaselinetoWeek16*

Treatment nTCLDL-CHDL-CTC/HDL-CTGLp(a)ApoBApoA-I

NIASPAN1000mgatbedtime41-3 -5 +18 -17 -21-13 -6 +9

NIASPAN2000mgatbedtime41-10-14 +22 -25 -28-27-16 +8

Placebo 400 -1 +4 -3 0 0 +1 +3

NIASPAN1500mgatbedtime76-8-12 +20 -20 -13-15-12 +8

Placebo 73+2 +1 +2 +1 +12+2 +1 +2

n=numberofpatientsatbaseline;

*MeanpercentchangefrombaselineforallNIASPANdoseswassignificantlydifferent( p<

0.05)fromplaceboforalllipidparametersshownexceptApoA-Iat2000mg.

Inadouble-blind,multi-center,forceddose-escalationstudy,monthly500mgincreasesinNIASPAN

doseresultedinincrementalreductionsofapproximately5%inLDL-CandApoBlevelsinthedaily

doserangeof500mgthrough2000mg(Table4).Womenagaintendedtohaveagreaterresponse

toNIASPANthanmen(see GenderEffect,below).

Table 4. Lipid Response in Dose-Escalation Study

MeanPercentChangefromBaseline*

Treatment nTCLDL-CHDL-CTC/HDL-CTGLp(a)ApoBApoA-I

Placebo ‡ 44-2 -1 +5 -7 -6 -5 -2 +4

NIASPAN 87

500mgatbedtime -2 -3 +10 -10 -5 -3 -2 +5

1000mgatbedtime -5 -9 +15 -17 -11 -12 -7 +8

1500mgatbedtime -11 -14 +22 -26 -28 -20 -15 +10

2000mgat

bedtime -12 -17 +26 -29 -35 -24 -16 +12

n=numberofpatientsenrolled;

Placebodatashownareafter24weeksofplacebotreatment.

*ForallNIASPANdosesexcept500mg,meanpercentchangefrombaselinewas

significantlydifferent( p<0.05)fromplaceboforalllipidparametersshownexceptLp(a)

andApoA-Iwhichweresignificantlydifferentfromplacebostartingwith1500mgand

2000mg,respectively.

Pooledresultsformajorlipidsfromthesethreeplacebo-controlledstudiesareshownbelow(Table5).

Table 5. Selected Lipid Response to NIASPANin Placebo-Controlled Clinical

Studies*

MeanBaselineandMedianPercentChangefromBaseline

(25 th ,75 th Percentiles)

NIASPAN

Dose n LDL-C HDL-C TG

1000mgatbedtime 104

Baseline(mg/dL) 218 45 172

PercentChange -7(-15,0) +14(+7,+23) -16(-34,+3)

1500mgatbedtime 120

Baseline(mg/dL) 212 46 171

PercentChange -13(-21,-4) +19(+9,+31) -25(-45,-2)

2000mgatbedtime 85

Baseline(mg/dL) 220 44 160

PercentChange -16(-26,-7) +22(+15,+34) -38(-52,-14)

*Representspooledanalysesofresults;minimumdurationontherapyateachdosewas

4weeks.

GenderEffect:Combineddatafromthethreeplacebo-controlledNIASPANstudiesinpatientswith

primaryhyperlipidemiaandmixeddyslipidemiasuggestthat,ateachNIASPANdoselevelstudied,

changesinlipidconcentrationsaregreaterforwomenthanformen(Table6).

Table 6. Effect of Gender on NIASPANDose Response

MeanPercentChangefromBaseline

NIASPAN n LDL-C HDL-C TG ApoB

Dose (M/F) M F M F M F M F

500mgatbedtime 50/37 -2 -5 +11 +8 -3 -9 -1 -5

1000mgatbedtime 76/52 -6* -11* +14 +20 -10-20 -5* -10*

1500mgatbedtime 104/59 -12 -16 +19 +24 -17-28-13 -15

2000mgatbedtime 75/53 -15 -18 +23 +26 -30-36-16 -16

n=numberofmale/femalepatientsenrolled.

*Percentchangesignificantlydifferentbetweengenders( p<0.05).

OtherPatientPopulations:Inadouble-blind,multi-center,19-weekstudythelipid-alteringeffectsof

NIASPAN(forcedtitrationto2000mgatbedtime)werecomparedtobaselineinpatientswhose

primarylipidabnormalitywasalowlevelofHDL-C(HDL-C≤40mg/dL,TG≤400mg/dL,andLDL-C

≤160,or<130mg/dLinthepresenceofCHD).Resultsareshownbelow(Table7).

Table 7. Lipid Response to NIASPANinPatients with LowHDL-C

MeanBaselineandMeanPercentChangefromBaseline*

nTCLDL-CHDL-CTC/HDL-CTGLp(a) ApoB ApoA-

I LpA-I ††

Baseline

(mg/dL) 88190120 31 6 194 8 106 105 32

Week19

(%Change) 71-3 0 +26 -22 -30-20 -9 +11 +20

n=numberofpatients

*Meanpercentchangefrombaselinewassignificantlydifferent( p<0.05)foralllipid

parametersshownexceptLDL-C.

n=72atbaselineand69atweek19.

†† n=30atbaselineandweek19.

AtNIASPAN2000mg/day,medianchangesfrombaseline(25th,75thpercentiles)forLDL-C,HDL-C,

andTGwere-3%(-14,+12%),+27%(+13,+38%),and-33%(-50,-19%),respectively.

14.3NIASPANandLovastatinClinicalStudies

CombinationNIASPANandLovastatinStudy:Inamulti-center,randomized,double-blind,parallel,

28-weekstudy,acombinationtabletofNIASPANandlovastatinwascomparedtoeachindividual

componentinpatientswithTypeIIaandIIbhyperlipidemia.Usingaforceddose-escalationstudy

design,patientsreceivedeachdoseforatleast4weeks.Patientsrandomizedtotreatmentwiththe

combinationtabletofNIASPANandlovastatininitiallyreceived500mg/20mg(expressedasmgof

niacin/mgoflovastatin)oncedailybeforebedtime.Thedosewasincreasedby500mgat4-week

intervals(basedontheNIASPANcomponent)toamaximumdoseof1000mg/20mginone-halfof

thepatientsand2000mg/40mgintheotherhalf.TheNIASPANmonotherapygroupunderwenta

similartitrationfrom500mgto2000mg.Thepatientsrandomizedtolovastatinmonotherapyreceived

20mgfor12weekstitratedto40mgforupto16weeks.Uptoathirdofthepatientsrandomizedto

thecombinationtabletofNIASPANandlovastatinorNIASPANmonotherapydiscontinuedpriorto

Week28.ResultsfromthisstudyshowedthatcombinationtherapydecreasedLDL-C,TGandLp(a),

andincreasedHDL-Cinadose-dependentfashion(Tables8,9,10,and11).Resultsfromthisstudy

forLDL-Cmeanpercentchangefrombaseline(theprimaryefficacyvariable)showedthat:

1. LDL-loweringwiththecombinationtabletofNIASPANandlovastatinwassignificantly

greaterthanthatachievedwithlovastatin40mgonlyafter28weeksoftitrationtoadoseof

2000mg/40mg( p<0.0001)

2. ThecombinationtabletofNIASPANandlovastatinatdosesof1000mg/20mgorhigher

achievedgreaterLDL-loweringthanNIASPAN( p<0.0001)

TheLDL-CresultsaresummarizedinTable8.

Table 8. LDL-Cmean percent change frombaseline

Week CombinationTabletofNIASPANand

Lovastatin NIASPAN Lovastatin

n* Dose LDL n*Dose LDL n*Dose LDL

(mg/mg) (mg) (mg)

Baseline57 – 190.9mg/dL 61– 189.7

mg/dL 61– 185.6

mg/dL

12 47 1000/20 -30% 461000 -3% 5620 -29%

16 45 1000/40 -36% 441000 -6% 5640 -31%

20 42 1500/40 -37% 431500 -12% 5440 -34%

28 42 2000/40 -42% 412000 -14% 5340 -32%

*n=numberofpatientsremainingintrialateachtimepoint

CombinationtherapyachievedsignificantlygreaterHDL-raisingcomparedtolovastatinandNIASPAN

monotherapyatalldoses(Table9).

Table 9. HDL-Cmean percent change frombaseline

Week CombinationTabletofNIASPANand

Lovastatin NIASPAN Lovastatin

n* Dose HDL n*DoseHDL n*DoseHDL

(mg/mg) (mg) (mg)

Baseline57 – 45mg/dL 61– 47

mg/dL 61– 43

mg/dL

12 47 1000/20 +20% 461000+14%5620 +3%

16 45 1000/40 +20% 441000+15%5640 +5%

20 42 1500/40 +27% 431500+22%5440 +6%

28 42 2000/40 +30% 412000+24%5340 +6%

*n=numberofpatientsremainingintrialateachtimepoint

Inaddition,combinationtherapyachievedsignificantlygreaterTGloweringatdosesof1000

mg/20mgorgreatercomparedtolovastatinandNIASPANmonotherapy(Table10).

Table 10. TGmedian percent change frombaseline

Week CombinationTabletofNIASPANand

Lovastatin NIASPAN Lovastatin

n* Dose TG n*Dose TG n*Dose TG

(mg/mg) (mg) (mg)

Baseline57 – 174mg/dL 61– 186

mg/dL 61– 171

mg/dL

12 47 1000/20 -32% 461000 -22%5620 -20%

16 45 1000/40 -39% 441000 -23%5640 -17%

20 42 1500/40 -44% 431500 -31%5440 -21%

28 42 2000/40 -44% 412000 -31%5340 -20%

*n=numberofpatientsremainingintrialateachtimepoint

TheLp(a)-loweringeffectsofcombinationtherapyandNIASPANmonotherapyweresimilar,andboth

weresuperiortolovastatin(Table11).TheindependenteffectofloweringLp(a)withNIASPANor

combinationtherapyontheriskofcoronaryandcardiovascularmorbidityandmortalityhasnotbeen

determined.

Table 11. Lp(a) median percentchangefrombaseline

Week CombinationTabletofNIASPANand

Lovastatin NIASPAN Lovastatin

n* Dose Lp(a) n*DoseLp(a)n*DoseLp(a)

(mg/mg) (mg) (mg)

Baseline57 – 34mg/dL 61– 41

mg/dL 60– 42

mg/dL

12 47 1000/20 -9% 461000 -8% 5520 +8%

16 45 1000/40 -9% 441000-12%5540 +8%

20 42 1500/40 -17% 431500-22%5340 +6%

28 42 2000/40 -22% 412000-32%5240 0%

*n=numberofpatientsremainingintrialateachtimepoint

14.4NIASPANandSimvastatinClinicalStudies

Inadouble-blind,randomized,multicenter,multi-national,active-controlled,24-weekstudy,thelipid

effectsofacombinationtabletofNIASPANandsimvastatinwerecomparedtosimvastatin20mgand

80mgin641patientswithtypeIIhyperlipidemiaormixeddyslipidemia.Followingalipidqualification

phase,patientswereeligibletoenteroneoftwotreatmentgroups.InGroupA,patientson

simvastatin20mgmonotherapy,withelevatednon-HDLlevelsandLDL-Clevelsatgoalperthe

NCEPguidelines,wererandomizedtooneofthreetreatmentarms:combinationtabletofNIASPAN

andsimvastatin1000/20mg,combinationtabletofNIASPANandsimvastatin2000/20mg,or

simvastatin20mg.InGroupB,patientsonsimvastatin40mgmonotherapy,withelevatednon-HDL

levelspertheNCEPguidelinesregardlessofattainmentofLDL-Cgoals,wererandomizedtooneof

threetreatmentarms:combinationtabletofNIASPANandsimvastatin1000/40mg,combination

tabletofNIASPANandsimvastatin2000/40mg,orsimvastatin80mg.Therapywasinitiatedatthe

500mgdoseofcombinationtabletofNIASPANandsimvastatinandincreasedby500mgeveryfour

weeks.Thuspatientsweretitratedtothe1000mgdoseofcombinationtabletofNIASPANand

simvastatinafterfourweeksandtothe2000mgdoseofcombinationtabletofNIASPANand

simvastatinafter12weeks.Allpatientsrandomizedtosimvastatinmonotherapyreceived50mg

immediate-releaseniacindailyinanattempttokeepthestudyfrombecomingunblindeddueto

flushinginthecombinationtabletofNIASPANandsimvastatingroups.Patientswereinstructedto

takeone325mgaspirinor200mgibuprofen30minutespriortotakingthedouble-blindmedication

tohelpminimizeflushingeffects.

InGroupA,theprimaryefficacyanalysiswasacomparisonofthemeanpercentchangeinnon-HDL

levelsbetweenthecombinationtabletofNIASPANandsimvastatin2000/20mgandsimvastatin20

mggroups,andifstatisticallysignificant,thenacomparisonwasconductedbetweenthecombination

tabletofNIASPANandsimvastatin1000/20mgandsimvastatin20mggroups.InGroupB,the

primaryefficacyanalysiswasadeterminationofwhetherthemeanpercentchangeinnon-HDLinthe

combinationtabletofNIASPANandsimvastatin2000/40mggroupwasnon-inferiortothemean

percentchangeinthesimvastatin80mggroup,andifso,whetherthemeanpercentchangeinnon-

HDLinthecombinationtabletofNIASPANandsimvastatin1000/40mggroupwasnon-inferiortothe

meanpercentchangeinthesimvastatin80mggroup.

InGroupA,thenon-HDL-CloweringwithcombinationtabletofNIASPANandsimvastatin2000/20

andcombinationtabletofNIASPANandsimvastatin1000/20wasstatisticallysignificantlygreater

thanthatachievedwithsimvastatin20mgafter24weeks( p<0.05;Table12).Thecompletionrate

after24weekswas72%forthecombinationtabletofNIASPANandsimvastatinarmsand88%for

thesimvastatin20mgarm.InGroupB,thenon-HDL-CloweringwithcombinationtabletofNIASPAN

andsimvastatin2000/40andcombinationtabletofNIASPANandsimvastatin1000/40wasnon-

inferiortothatachievedwithsimvastatin80mgafter24weeks(Table13).Thecompletionrateafter

24weekswas78%forthecombinationtabletofNIASPANandsimvastatinarmsand80%forthe

simvastatin80mgarm.

ThecombinationtabletofNIASPANandsimvastatinwasnotsuperiortosimvastatininloweringLDL-

CineitherGroupAorGroupB.However,thecombinationtabletofNIASPANandsimvastatinwas

superiortosimvastatininbothgroupsinloweringTGandraisingHDL(Tables14and15).

Table 12. Non-HDL Treatment Response Following 24-Week Treatment Mean

Percent Change fromSimvastatin 20-mg Treated Baseline

GroupA

CombinationTabletof

NIASPANandSimvastatin

2000/20 CombinationTabletof

NIASPANandSimvastatin

1000/20 Simvastatin20

Week n a Dose

(mg/mg) Non-

HDL b n a Dose

(mg/mg) Non-

HDL b n a Dose

(mg/mg) Non-

HDL b

Baseline 56 – 163.1

mg/dL 108 – 164.8

mg/dL 102 – 163.7

mg/dL

4 52 500/20 -12.9% 86 500/20 -12.8% 91 20 -8.3%

8 46 1000/20-17.5% 91 1000/20-15.5% 95 20 -8.3%

12 46 1500/20-18.9% 90 1000/20-14.8% 96 20 -6.4%

24 40 2000/20-19.5% † 78 1000/20-13.6% † 90 20 -5.0%

Dropouts

byweek

24: 28.6% 27.8% 11.8%

a n=numberofsubjectswithvaluesintheanalysiswindowateachtimepoint

b Thepercentchangefrombaselineisthemodel-basedmeanfromarepeatedmeasures

mixedmodelwithnoimputationformissingdatafromstudydropouts.

significantvs.simvastatin20mgattheprimaryendpoint(Week24), p<0.05

Table 13. Non-HDL Treatment Response Following 24-Week Treatment Mean

Percent Change fromSimvastatin 40-mg TreatedBaseline

GroupB

CombinationTabletof

NIASPANand

Simvastatin2000/40 CombinationTabletof

NIASPANand

Simvastatin1000/40 Simvastatin80

Week n a Dose

(mg/mg) Non-

HDL b n a Dose

(mg/mg) Non-

HDL b n a Dose

(mg/mg) Non-

HDL b

Baseline 98 – 144.4 111 – 141.2 113 – 134.5

mg/dL mg/dL mg/dL

4 96 500/40 -6.0% 108 500/40 -5.9% 110 80 -11.3%

8 93 1000/40-15.5%100 1000/40-16.2%104 80 -13.7%

12 90 1500/40-18.4% 97 1000/40-12.6%100 80 -9.5%

24 80 2000/40-7.6% c 82 1000/40-6.7% d 90 80 -6.0%

Dropouts

byweek

24: 18.4% 26.1% 20.4%

a n=numberofsubjectswithvaluesintheanalysiswindowateachtimepoint

b Thepercentchangefrombaselineisthemodel-basedmeanfromarepeatedmeasures

mixedmodelwithnoimputationformissingdatafromstudydropouts.

non-inferiortosimvastatin80arm;95%confidenceintervalofmeandifferenceinnon-

HDLforthecombinationtabletofNIASPANandsimvastatin2000/40vs.simvastatin80

is(-7.7%,4.5%)

non-inferiortosimvastatin80arm;95%confidenceintervalofmeandifferenceinnon-

HDLforcombinationtabletofNIASPANandsimvastatin1000/40vs.combinationtablet

ofNIASPANandsimvastatin80is(-6.6%,5.3%)

Table 14. Mean Percent Change fromBaseline to Week24 in LipoproteinLipid

Levels

TreatmentGroupA

TREATMENT NLDL-CTotal-

C HDL-

C TG a ApoB

Baseline(mg/dL)* 266120 207 43 209 102

Simvastatin20mg 102-6.7%-4.5%7.8% -

15.3% -5.6%

CombinationTabletofNIASPANand

Simvastatin1000/20 108 -

11.9% -8.8%20.7% -

26.5% -

13.2%

CombinationTabletofNIASPANand

Simvastatin2000/20 56 -

14.3% -11.1%29.0% -

38.0% -

18.5%

eithertreatmentnaïveorafterreceivingsimvastatin20mg

mediansarereportedforTG

Table 15. Mean Percent Change fromBaseline to Week24 in LipoproteinLipid

Levels

TreatmentGroupB

TREATMENT NLDL-CTotal-

C HDL-

C TG a ApoB

Baseline(mg/dL)* 322108 187 47 145 93

Simvastatin80mg 113 -

11.4% -6.2%0.1%0.3%-7.5%

CombinationTabletofNIASPANand

Simvastatin1000/40 111-7.1%-3.1%15.4% -

22.8% -7.7%

CombinationTabletofNIASPANand

Simvastatin2000/40 98-5.1-1.6%24.4% -

31.8% -

10.5%

afterreceivingsimvastatin40mg

mediansarereportedforTG

16HOWSUPPLIED/STORAGEANDHANDLING

NIASPANtabletsaresuppliedasunscored,medium-orange,film-coated,capsule-shaped(containing

500or750mgofniacin)orovalshaped(containing1000mgofniacin)tablets,inanextended-

releaseformulation.TabletsareprintedwiththeAbbott‘A’logoandthetabletstrength(500,750or

1000).Tabletsaresuppliedinbottlesof90tablets.

Niaspan500mgExtendedReleaseFilmCoatedTablets

Niaspan750mgExtendedReleaseFilmCoatedTablets

Niaspan1000mgExtendedReleaseFilmCoatedTablets

Storage:Storeatroomtemperaturebelow25°C.

Manufacturer:AbbottLaboratories,U.S.A.

LicenseHolder:AbbottMedicalLaboratoriesLtd.P.O.Box58099,TelAviv

TheformatofthisleafletwasdeterminedbytheMinistryofHealthanditscontentwascheckedand

approved

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