Indications and Usage: Limitations of Use (1) 02/2013 Warnings and Precautions, Mortality and Coronary Heart Disease Morbidity (5.1) 02/2013
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.
Niacin extended-release tablets, USP are 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.
Niacin extended-releasein combination with simvastatin or lovastatin is indicated for the treatment of primary hyperlipidemia and mixed dyslipidemia when treatment with niacin extended-release, simvastatin, or lovastatin monotherapy is considered inadequate.
In patients with a history of myocardial infarction and hyperlipidemia, niacin is indicated to reduce the risk of recurrent nonfatal myocardial infarction.
In patients with a history of coronary artery disease (CAD) and hyperlipidemia, niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease.
Niacin extended-release in combination with a bile acid binding resin is indicated to reduce elevated TC and LDL-C levels in adult patients with primary hyperlipidemia.
Niacin is also indicated as adjunctive therapy for treatment of adult patients with severe hypertriglyceridemia who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them.
Limitations of Use
No incremental benefit of niacin extended-release coadministered with simvastatin or lovastatin on cardiovascular morbidity and mortality over and above that demonstrated for niacin, simvastatin, or lovastatin monotherapy has been established.
Niacin extended-release, at doses of 1,500 to 2,000 mg/day, in combination with simvastatin, did not reduce the incidence of cardiovascular events more than simvastatin in a randomized controlled trial of patients with cardiovascular disease and mean baseline LDL-C levels of 74 mg per deciliter [see Warnings and Precautions (5.1)].
Niacin extended-release tablets, USP should be taken at bedtime, after a low-fat snack, and doses should be individualized according to patient response. Therapy with niacin extended-release tablets, USP must be initiated at 500 mg at bedtime in order to reduce the incidence and severity of side effects which may occur during early therapy. The recommended dose escalation is shown in Table 1 below.
| Week(s) | Daily dose | Niacin Extended-Release Dosage | ||
| INITIAL TITRATION SCHEDULE | 1 to 4 | 500 mg | 1 niacin extended-release 500 mg tablet at bedtime | |
| 5 to 8 | 1000 mg | 1 niacin extended-release 1000 mg tablet or 2 niacin extended-release 500 mg tablets at bedtime | ||
| 1500 mg | 2 niacin extended-release 750 mg tablets or 3 niacin extended-release 500 mg tablets at bedtime | |||
| 2000 mg | 2 niacin extended-release 1000 mg tablets or 4 niacin extended-release 500 mg tablets at bedtime | |||
Maintenance Dose
The daily dosage of niacin extended-release tablets, USP should not be increased by more than 500 mg in any 4-week period. The recommended maintenance dose is 1000 mg (two 500 mg tablets or one 1000 mg tablet) to 2000 mg (two 1000 mg tablets or four 500 mg tablets) once daily at bedtime. Doses greater than 2000 mg daily are not recommended. Women may respond at lower niacin extended-release tablets, USP doses than men [see Clinical Studies (14.2)].
Single-dose bioavailability studies have demonstrated that two of the 500 mg and one of the 1000 mg tablet strengths are interchangeable but three of the 500 mg and two of the 750 mg tablet strengths are not interchangeable.
If lipid response to niacin extended-release tablets, USP alone is insufficient or if higher doses of niacin extended-release tablets, USP are not well tolerated, some patients may benefit from combination therapy with a bile acid binding resin or statin [see Drug Interactions (7.3), Concomitant Therapy belowand Clinical Studies (14.3, 14.4)].
Flushing of the skin [see Adverse Reactions (6.1)] may be reduced in frequency or severity by pretreatment with aspirin (up to the recommended dose of 325 mg taken 30 minutes prior to niacin extended-release tablets, USP dose). Tolerance to this flushing develops rapidly over the course of several weeks. Flushing, pruritus, and gastrointestinal distress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of niacin extended-release tablets, USP ingestion.
Equivalent doses of niacin extended-release tablets, USP should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin [see Warnings and Precautions (5)]. Patients previously receiving other niacin products should be started with the recommended niacin extended-release tablets, USP titration schedule (see Table 1), and the dose should subsequently be individualized based on patient response.
If niacin extended-release tablets, USP therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase (see Table 1).
Niacin extended-release tablets, USP should be taken whole and should not be broken, crushed or chewed before swallowing.
Concomitant Therapy
Concomitant Therapy with Lovastatin or Simvastatin
Patients already receiving a stable dose of lovastatin or simvastatin who require further TG-lowering or HDL-raising (e.g., to achieve NCEP non-HDL-C goals), may receive concomitant dosage titration with niacin extended-release tablets, USP per niacin extended-release tablets, USP recommended initial titration schedule [see Dosage and Administration (2)]. For patients already receiving a stable dose of niacin extended-release tablets, USP who require further LDL-lowering (e.g., to achieve NCEP LDL-C goals), the usual recommended starting dose of lovastatin and simvastatin is 20 mg once a day. Dose adjustments should be made at intervals of 4 weeks or more. Combination therapy with niacin extended-release tablets, USP and lovastatin or niacin extended-release tablets, USP and simvastatin should not exceed doses of 2000 mg niacin extended-release tablets, USP and 40 mg lovastatin or simvastatin daily.
Dosage in Patients with Renal or Hepatic Impairment
Use of niacin extended-release tablets, USP in patients with renal or hepatic impairment has not been studied. Niacin extended-release tablets, USP are contraindicated in patients with significant or unexplained hepatic dysfunction. Niacin extended-release tablets, USP should be used with caution in patients with renal impairment [see Warnings and Precautions (5)].
500 mg unscored, pink, film-coated, capsule-shaped tablets
750 mg unscored, pink, film-coated, capsule-shaped tablets
1000 mg unscored, pink, film-coated, capsule-shaped tablets
Niacin extended-release tablets are contraindicated in the following conditions:
Active liver disease or unexplained persistent elevations in hepatic transaminases [see Warnings and Precautions ( 5.3 )]
Patients with active peptic ulcer disease
Patients with arterial bleeding
Hypersensitivity to niacin or any component of this medication [see Adverse Reactions ( 6.1 )]
Niacinextended-release tablets preparations should not be substituted for equivalentdoses of immediate-release (crystalline) niacin. For patients switching fromimmediate-release niacin to niacin extended-release tablets, therapy with niacinextended-release tablets should be initiated with low doses (i.e., 500 mg at bedtime)and the niacin extended-release tablets dose should then be titrated to thedesired therapeutic response [see Dosageand Administration (2)].
Caution should also be used when niacinextended-releaseis used in patients with unstable angina or in the acute phase of an MI,particularly when such patients are also receiving vasoactive drugs such asnitrates, calcium channel blockers, or adrenergic blocking agents.
Niacin is rapidly metabolized bythe liver, and excreted through the kidneys. Niacin extended-releaseis contraindicated in patients with significant or unexplained hepaticimpairment [see Contraindications (4) andWarnings and Precautions (5.3)] and should be used with caution in patientswith renal impairment. Patients with a past history of jaundice, hepatobiliarydisease, or peptic ulcer should be observed closely during niacin extended-releasetherapy.
The AtherothrombosisIntervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact onGlobal Health Outcomes (AIM-HIGH) trial was a randomized placebo-controlledtrial of 3414 patients with stable, previously diagnosed cardiovasculardisease. Mean baseline lipid levels were LDL-C 74 mg/dL, HDL-C 35 mg/dL,non-HDL-C 111 mg/dL and median triglyceride level of 163 to 177 mg/dL.Ninety-four percent of patients were on background statin therapy prior toentering the trial. All participants received simvastatin, 40 to 80 mg per day,plus ezetimibe 10 mg per day if needed, to maintain an LDL-C level of 40 to 80mg/dL, and were randomized to receive niacin extended-release 1,500 to 2,000 mg/day (n=1718) or matchingplacebo (IR Niacin, 100 to 150 mg, n=1696). On-treatment lipid changes at twoyears for LDL-C were -12% for the simvastatin plus niacin extended-release group and -5.5% for the simvastatin plusplacebo group. HDL-C increased by 25% to 42 mg/dL in the simvastatin plusniacin extended-release group and by 9.8% to 38 mg/dL in the simvastatin plus placebo group(P<0.001). Triglyceride levels decreased by 28.6% in the simvastatin plusniacin extended-release group and by 8.1% in the simvastatin plus placebo group. The primaryoutcome was an ITT composite of the first study occurrence of coronary heartdisease death, nonfatal myocardial infarction, ischemic stroke, hospitalizationfor acute coronary syndrome or symptom-driven coronary or cerebralrevascularization procedures. The trial was stopped after a mean follow-upperiod of 3 years owing to a lack of efficacy. The primary outcome occurred in282 patients in the simvastatin plus niacin extended-release group (16.4%) and in 274 patients in thesimvastatin plus placebo group (16.2%) (HR 1.02 [95% CI, 0.87 to 1.21], P=0.79.In an ITT analysis, there were 42 cases of first occurrence of ischemic strokereported, 27 (1.6%) in the simvastatin plus niacin extended-release group and 15 (0.9%) in the simvastatin plusplacebo group, a non-statistically significant result (HR 1.79, [95%CI = 0.95to 3.36], p=0.071). The on-treatment ischemic stroke events were 19 for thesimvastatin plus niacin extended-release group and 15 for the simvastatin plus placebo group [see Adverse Reactions (6.1)].
Cases of rhabdomyolysis have beenassociated with concomitant administration of lipid-altering doses (>=1 g/day)of niacin and statins. Physicians contemplating combined therapy with statinsand niacin extended-releaseshould carefully weigh the potential benefits and risks and should carefullymonitor patients for any signs and symptoms of muscle pain, tenderness, orweakness, particularly during the initial months of therapy and during anyperiods of upward dosage titration of either drug. Periodic serum creatinephosphokinase (CPK) and potassium determinations should be considered in suchsituations, but there is no assurance that such monitoring will prevent theoccurrence of severe myopathy.
The risk for myopathy and rhabdomyolysis are increasedwhen lovastatin or simvastatin are coadministered with niacin extended-release, particularly in elderly patients and patients withdiabetes, renal failure, or uncontrolled hypothyroidism.
Casesof severe hepatic toxicity, including fulminant hepatic necrosis, have occurredin patients who have substituted sustained-release (modified-release,timed-release) niacin products for immediate-release (crystalline) niacin atequivalent doses.
Niacin extended - release should be used with caution in patients who consume substantial quantities ofalcohol and/or have a past history of liver disease. Active liver diseases orunexplained transaminase elevations are contraindications to the use of niacin extended - release .
Niacin preparations have been associatedwith abnormal liver tests. In three placebo-controlled clinical trialsinvolving titration to final daily niacin extended-releasedoses ranging from 500 mgto 3000 mg, 245 patients received niacin extended-releasefor a mean duration of 17 weeks. No patient with normal serum transaminaselevels (AST, ALT) at baseline experienced elevations to more than 3 times theupper limit of normal (ULN) during treatment with niacin extended-release.In these studies, fewer than 1% (2/245) of niacin extended-releasepatients discontinued due to transaminase elevations greater than 2 times theULN.
In three safety and efficacystudies with a combination tablet of niacin extended-releaseand lovastatin involving titration to final daily doses (expressed as mg ofniacin/mg of lovastatin) 500 mg/10 mg to 2500 mg/40 mg, ten of 1028patients (1%) experienced reversible elevations in AST/ALT to more than 3 timesthe ULN. Three of ten elevations occurred at doses outside the recommendeddosing limit of 2000 mg/40 mg; no patient receiving 1000 mg/20 mg had 3-foldelevations in AST/ALT.
Niacin extended-release andsimvastatin can cause abnormal liver tests. In a simvastatin-controlled, 24week study with a fixed dose combination of niacin extended-releaseand simvastatin in 641 patients, there were no persistent increases (more than3x the ULN) in serum transaminases. In three placebo-controlled clinicalstudies of extended-release niacin there were no patients with normal serumtransaminase levels at baseline who experienced elevations to more than 3x theULN. Persistent increases (more than 3x the ULN) in serum transaminases haveoccurred in approximately 1% of patients who received simvastatin in clinicalstudies. When drug treatment was interrupted or discontinued in these patients,the transaminases levels usually fell slowly to pretreatment levels. Theincreases were not associated with jaundice or other clinical signs orsymptoms. There was no evidence of hypersensitivity.
In the placebo-controlledclinical trials and the long-term extension study, elevations in transaminasesdid not appear to be related to treatment duration; elevations in AST levelsdid appear to be dose related. Transaminase elevations were reversible upondiscontinuation of niacin extended-release.
Liver function tests should be performed on allpatients during therapy with niacin extended-release. Serum transaminase levels, including AST and ALT(SGOT and SGPT), should be monitored before treatment begins, every 6 to 12weeks for the first year, and periodically thereafter (e.g., at approximately6-month intervals). Special attention should be paid to patients who developelevated serum transaminase levels, and in these patients, measurements shouldbe repeated promptly and then performed more frequently. If the transaminaselevels show evidence of progression, particularly if they rise to 3 times ULNand are persistent, or if they are associated with symptoms of nausea, fever,and/or malaise, the drug should be discontinued.
Increasein Blood Glucose:
Niacin treatment can increasefasting blood glucose. Frequent monitoring of blood glucose should be performedto ascertain that the drug is producing no adverse effects. Diabetic patients may experience a dose-related increase in glucoseintolerance. Diabetic or potentially diabetic patients should be observedclosely during treatment with niacin extended-release,particularly during the first few months of use or dose adjustment; adjustmentof diet and/or hypoglycemic therapy may be necessary.
Reduction inplatelet count:
Niacin extended-releasehas been associated with small but statistically significant dose-relatedreductions in platelet count (mean of -11% with 2000 mg). Caution should beobserved when niacin extended-releaseis administered concomitantly with anticoagulants; platelet counts should bemonitored closely in such patients.
Increase inProthrombin Time (PT):
Niacin extended-releasehas been associated with small but statistically significant increases inprothrombin time (mean of approximately +4%); accordingly, patients undergoingsurgery should be carefully evaluated. Caution should be observed when niacin extended-releaseis administered concomitantly with anticoagulants; prothrombin time should bemonitored closely in such patients.
Increasein Uric Acid:
Elevated uric acid levels haveoccurred with niacin therapy, therefore use with caution in patientspredisposed to gout.
Decreasein Phosphorus:
In placebo-controlled trials, niacin extended-release has been associated with small but statisticallysignificant, dose-related reductions in phosphorus levels (mean of -13% with2000 mg). Although these reductions were transient, phosphorus levelsshould be monitored periodically in patients at risk for hypophosphatemia.
Because clinical studies are conducted underwidely varying conditions, adverse reaction rates observed in the clinicalstudies of a drug cannot be directly compared to rates in the clinical studiesof another drug and may not reflect the rates observed in practice.
In the placebo-controlledclinical trials database of 402 patients (age range 21 to 75 years, 33% women,89% Caucasians, 7% Blacks, 3% Hispanics, 1% Asians) with a median treatmentduration of 16 weeks, 16% of patients on niacin extended-releaseand 4% of patients on placebo discontinued due to adverse reactions. The mostcommon adverse reactions in the group of patients treated with niacin extended-releasethat led to treatment discontinuation and occurred at a rate greater thanplacebo were flushing (6% vs. 0%), rash (2% vs. 0%), diarrhea (2% vs. 0%),nausea (1% vs. 0%), and vomiting (1% vs. 0%). The most commonly reportedadverse reactions (incidence >5% and greater than placebo) in the niacin extended-releasecontrolled clinical trial database of 402 patients were flushing, diarrhea,nausea, vomiting, increased cough and pruritus.
Inthe placebo-controlled clinical trials, flushing episodes (i.e., warmth, redness,itching and/or tingling) were the most common treatment-emergent adversereactions (reported by as many as 88% of patients) for niacin extended-release.Spontaneous reports suggest that flushing may also be accompanied by symptomsof dizziness, tachycardia, palpitations, shortness of breath, sweating, burningsensation/skin burning sensation, chills, and/or edema, which in rare cases maylead to syncope. In pivotal studies, 6% (14/245) of niacin extended-release patientsdiscontinued due to flushing. In comparisons of immediate-release (IR) niacinand niacin extended-release tablets, although the proportion of patients whoflushed was similar, fewer flushing episodes were reported by patients whoreceived niacin extended-release tablets. Following 4 weeks of maintenancetherapy at daily doses of 1500 mg, the incidence of flushing over the4-week period averaged 8.6 events per patient for IR niacin versus 1.9following niacin extended-release tablets.
Other adverse reactions occurringin >=5% of patients treated with niacin extended-release tablets and at anincidence greater than placebo are shown in Table 2 below.
| Placebo-Controlled Studies Niacin Extended-Release Tablets Treatment | |||||
| Recommended Daily Maintenance Doses | |||||
| Placebo (n = 157) % | 500 mg (n = 87) % | 1000 mg (n = 110) % | 1500 mg (n = 136) % | 2000 mg (n = 95) % | |
| Gastrointestinal Disorders | |||||
| 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 |
| Skin and Subcutaneous Tissue | |||||
| Disorders | |||||
| Pruritus | 2 | 8 | 0 | 3 | 0 |
| Rash | 0 | 5 | 5 | 5 | 0 |
| Vascular Disorders | |||||
| Flushing | 19 | 68 | 69 | 63 | 55 |
| Note: Percentages are calculated from the total number of patients in each column. | |||||
In general, the incidence ofadverse events was higher in women compared to men.
Atherothrombosis Interventionin Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global HealthOutcomes (AIM-HIGH)
In AIM-HIGH involving 3,414 patients (mean ageof 64 years, 15% women, 92% Caucasians, 34% with diabetes mellitus) withstable, previously diagnosed cardiovascular disease, all patients receivedsimvastatin, 40 to 80 mg per day, plus ezetimibe 10 mg per day if needed, tomaintain an LDL-C level of 40 to 80 mg/dL, and were randomized to receiveniacin extended-release 1,500to 2,000 mg/day (n=1718) or matching placebo (IR Niacin, 100 mg to 150 mg,n=1696). The incidence of the adverse reactions of "blood glucose increased"(6.4% vs. 4.5%) and "diabetes mellitus" (3.6% vs. 2.2%) was significantlyhigher in the simvastatin plus niacin extended-release group as compared to the simvastatin plus placebogroup. There were 5 cases of rhabdomyolysis reported, 4 (0.2%) in thesimvastatin plus niacin extended-release groupand one (<0.1%) in the simvastatin plus placebo group [see Warnings andPrecautions (5.1)].
Because the below reactions arereported voluntarily from a population of uncertain size, it is generally notpossible to reliably estimate their frequency or establish a causalrelationship to drug exposure.
The following additional adversereactions have been identified during post-approval use of niacinextended-release tablets:
Hypersensitivity reactions,including anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema,larynx edema, face edema, peripheral edema, laryngismus, and vesiculobullousrash; maculopapular rash; dry skin; tachycardia; palpitations; atrialfibrillation; other cardiac arrhythmias; syncope; hypotension; posturalhypotension; blurred vision; macular edema; peptic ulcers; eructation; flatulence; hepatitis; jaundice; decreased glucose tolerance; gout; myalgia; myopathy; dizziness; insomnia; asthenia; nervousness; paresthesia; dyspnea; sweating; burning sensation/skin burning sensation; skin discoloration, andmigraine.
ClinicalLaboratory Abnormalities
Chemistry: Elevations in serumtransaminases [see Warnings and Precautions(5.3)], LDH, fasting glucose, uric acid, total bilirubin, amylase andcreatine kinase, and reduction in phosphorus.
Hematology:Slight reductions in platelet counts and prolongation in prothrombin time [see Warnings and Precautions (5.4)].
Statins: Caution should be used when prescribing niacin with statins as these agents can increase risk of myopathy/rhabdomyolysis. ( 5.2 , 7.1 )
Bile Acid Sequestrants: Bile acid sequestrants have a high niacin-binding capacity and should be taken at least 4 to 6 hours before niacin extended-release administration. ( 7.2 )
Caution should be used when prescribing niacin(>=1 gm/day) with statins as these drugs can increase risk ofmyopathy/rhabdomyolysis. Combination therapy with niacin extended-release and lovastatin or niacin extended-release and simvastatin should not exceed doses of 2000 mgniacin extended-release and40 mg lovastatin or simvastatin daily. [seeWarnings and Precautions (5) and Clinical Pharmacology (12.3)].
An in vitro study results suggest that the bile acid-binding resinshave high niacin binding capacity. Therefore, 4 to 6 hours, or as great aninterval as possible, should elapse between the ingestion of bile acid-bindingresins and the administration of niacin extended-release [see Clinical Pharmacology (12.3)].
Concomitant aspirin may decreasethe metabolic clearance of nicotinic acid. The clinical relevance of thisfinding is unclear.
Niacin may potentiate the effectsof ganglionic blocking agents and vasoactive drugs resulting in posturalhypotension.
Vitamins or other nutritional supplements containing large doses of niacin or related compounds such as nicotinamide may potentiate the adverse effects of niacin extended-release.
Niacin may produce false elevations in somefluorometric determinations of plasma or urinary catecholamines. Niacin mayalso give false-positive reactions with cupric sulfate solution (Benedict'sreagent) in urine glucose tests.
Renal impairment: Niacin extended-release tablets should be used with caution in patients with renal impairment. ( 5 , 8.6 )
Hepatic impairment: Niacin extended-release tablets are contraindicated in active liver disease or significant or unexplained hepatic dysfunction or unexplained elevations of serum transaminases. ( 4 , 5 , 5.3 , 8.7 )
Pregnancy Category C.
Animal reproduction studies havenot been conducted with niacin or with niacin extended-release tablets. It isalso not known whether niacin at doses typically used for lipid disorders cancause fetal harm when administered to pregnant women or whether it can affectreproductive capacity. If a woman receiving niacin for primary hyperlipidemia becomespregnant, the drug should be discontinued. If a woman being treated with niacinfor hypertriglyceridemia conceives, the benefits and risks of continued therapyshould be assessed on an individual basis.
All statins are contraindicatedin pregnant and nursing women. When niacin extended-release isadministered with a statin in a woman of childbearing potential, refer to thepregnancy category and product labeling for the statin.
Niacin is excreted into human milk but the actual infant dose or infant dose as a percent of the maternal dose is not known. Because of the potential for serious adverse reactions in nursing infants from lipid-altering doses of nicotinic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. No studies have been conducted with niacin extended-release tablets in nursing mothers.
Safety and effectiveness of niacin therapy inpediatric patients (<=16 years) have not been established.
Of 979 patients in clinical studies of niacin extended-release, 21% of the patients were age 65 and over. No overalldifferences in safety and effectiveness were observed between these patientsand younger patients, and other reported clinical experience has not identifieddifferences in responses between the elderly and younger patients, but greatersensitivity of some older individuals cannot be ruled out.
No studies have been performed in thispopulation. Niacin extended-release shouldbe used with caution in patients with renal impairment [see Warnings and Precautions (5)].
No studies have been performed in thispopulation. Niacin extended-release shouldbe used with caution in patients with a past history of liver disease and/orwho consume substantial quantities of alcohol. Active liver disease,unexplained transaminase elevations and significant or unexplained hepaticdysfunction are contraindications to the use of niacin extended-release [seeContraindications (4) and Warnings and Precautions (5.3)].
Data from the clinical trials suggest that womenhave a greater hypolipidemic response than men at equivalent doses of niacin extended-release.
Supportive measures should be undertaken in the event of an overdose.
Niacin extended-release tablet, USP contains niacin, which at therapeutic doses is an antihyperlipidemic agent. Niacin (nicotinic acid, or 3-pyridinecarboxylic acid) is a white, crystalline powder, sparingly soluble in water, with the following structural formula:
Niacin extended-release tablets, USP are unscored, pink, film-coated tablets for oral administration and are available in three tablet strengths containing 500 mg, 750 mg, and 1000 mg niacin USP. Niacin extended-release tablets, USP also contain the inactive ingredients hypromellose, hydrogenated vegetable oil Type I, glyceryl behenate, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol-partially hydrolyzed, titanium dioxide, polyethylene glycol, talc, iron oxide red and iron oxide yellow.USP Dissolution Test Pending
The mechanism by which niacin alters lipidprofiles has not been well defined. It may involve several actions includingpartial inhibition of release of free fatty acids from adipose tissue, andincreased lipoprotein lipase activity, which may increase the rate ofchylomicron triglyceride removal from plasma. Niacin decreases the rate ofhepatic synthesis of VLDL and LDL, and does not appear to affect fecalexcretion of fats, sterols, or bile acids.
Niacin functions in the bodyafter conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzymesystem. Niacin (but not nicotinamide) in gram doses reduces total cholesterol(TC), low density lipoprotein cholesterol (LDL-C), and triglycerides (TG), andincreases high-density lipoprotein cholesterol (HDL-C). The magnitude ofindividual lipid and lipoprotein responses may be influenced by the severityand type of underlying lipid abnormality. The increase in HDL-C is associatedwith an increase in apolipoprotein A-I (Apo A-I) and a shift in thedistribution of HDL subfractions. These shifts include an increase in the HDL2:HDL3ratio, and an elevation in lipoprotein A-I (Lp A-I, an HDL-C particlecontaining only Apo A-I). Niacin treatment also decreases serum levels ofapolipoprotein B-100 (Apo B), the major protein component of the verylow-density lipoprotein (VLDL) and LDL fractions, and of Lp(a), a variant formof LDL independently associated with coronary risk. In addition, preliminaryreports suggest that niacin causes favorable LDL particle size transformations,although the clinical relevance of this effect requires further investigation.The effect of niacin-induced changes in lipids/proteins on cardiovascularmorbidity or mortality in individuals without preexisting coronary disease hasnot been established.
A variety of clinical studieshave demonstrated that elevated levels of TC, LDL-C, and Apo B promote humanatherosclerosis. Similarly, decreased levels of HDL-C are associated with thedevelopment of atherosclerosis. Epidemiological investigations have establishedthat cardiovascular morbidity and mortality vary directly with the level ofTotal-C and LDL-C, and inversely with the level of HDL-C.
Like LDL, cholesterol-enriched triglyceride-richlipoproteins, including VLDL, intermediate-density lipoprotein (IDL), and theirremnants, can also promote atherosclerosis. Elevated plasma TG are frequentlyfound in a triad with low HDL-C levels and small LDL particles, as well as inassociation with non-lipid metabolic risk factors for coronary heart disease(CHD). As such, total plasma TG has not consistently been shown to be anindependent risk factor for CHD. Furthermore, the independent effect of raisingHDL-C or lowering TG on the risk of coronary and cardiovascular morbidity andmortality has not been determined.
Absorption
Due to extensive and saturablefirst-pass metabolism, niacin concentrations in the general circulation aredose dependent and highly variable. Time to reach the maximum niacin plasmaconcentrations was about 5 hours following niacin extended-release tablets. Toreduce the risk of gastrointestinal (GI) upset, administration of niacinextended-release tablets with a low-fat meal or snack is recommended.
Single-dose bioavailabilitystudies have demonstrated that the 500 mg and 1000 mg tablet strengths aredosage form equivalent but the 500 mg and 750 mg tablet strengths are notdosage form equivalent.
Metabolism
The pharmacokinetic profile ofniacin is complicated due to extensive first-pass metabolism that is dose-ratespecific and, at the doses used to treat dyslipidemia, saturable. In humans,one pathway is through a simple conjugation step with glycine to formnicotinuric acid (NUA). NUA is then excreted in the urine, although there maybe a small amount of reversible metabolism back to niacin. The other pathwayresults in the formation of nicotinamide adenine dinucleotide (NAD). It isunclear whether nicotinamide is formed as a precursor to, or following thesynthesis of, NAD. Nicotinamide is further metabolized to at leastN-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is furthermetabolized to two other compounds, N-methyl-2-pyridone-5-carboxamide (2PY) andN-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears topredominate over 4PY in humans. At the doses used to treat hyperlipidemia,these metabolic pathways are saturable, which explains the nonlinearrelationship between niacin dose and plasma concentrations followingmultiple-dose niacin extended-release tablets administration.
Nicotinamide does not havehypolipidemic activity; the activity of the other metabolites is unknown.
Elimination
Following single and multipledoses, approximately 60 to 76% of the niacin dose administered as niacinextended-release tablets was recovered in urine as niacin and metabolites; upto 12% was recovered as unchanged niacin after multiple dosing. The ratio ofmetabolites recovered in the urine was dependent on the dose administered.
PediatricUse
No pharmacokinetic studies havebeen performed in this population (<=16 years) [see Use in Specific Populations (8.4)].
Geriatric Use
No pharmacokinetic studies havebeen performed in this population (> 65 years) [see Use in Specific Populations (8.5)].
RenalImpairment
No pharmacokinetic studies havebeen performed in this population. Niacin extended-release tablets should beused with caution in patients with renal disease [see Warnings and Precautions (5 )].
Hepatic Impairment
No pharmacokinetic studies havebeen performed in this population. Active liver disease, unexplainedtransaminase elevations and significant or unexplained hepatic dysfunction arecontraindications to the use of niacin extended-release tablets [see Contraindications (4) and Warnings andPrecautions (5.3)].
Gender Steady-stateplasma concentrations of niacin and metabolites after administration of niacinextended-release tablets are generally higher in women than in men, with themagnitude of the difference varying with dose and metabolite. This genderdifferences observed in plasma levels of niacin and its metabolites may be dueto gender-specific differences in metabolic rate or volume of distribution.Recovery of niacin and metabolites in urine, however, is generally similar formen and women, indicating that absorption is similar for both genders [see Gender (8.8)].
Druginteractions
Fluvastatin Niacin did notaffect fluvastatin pharmacokinetics [seeDrug Interactions (7.1)].
Lovastatin
When niacin extended-release 2000mg and lovastatin 40 mg were co-administered, niacin extended-release increasedlovastatin Cmax and AUC by 2% and 14%, respectively, and decreasedlovastatin acid Cmax and AUC by 22% and 2%, respectively. Lovastatinreduced niacin extended-release bioavailabilityby 2 to 3% [see Drug Interactions ( 7.1)].
Simvastatin When niacin extended-release 2000mg and simvastatin 40 mg were co-administered, niacin extended-release increasedsimvastatin Cmax and AUC by 1% and 9%, respectively, and simvastatinacid Cmax and AUC by 2% and 18%, respectively. Simvastatin reduced niacin extended-release bioavailabilityby 2% [see Drug Interactions ( 7.1)].
Bile Acid Sequestrants
An in vitro study was carried out investigating the niacin-bindingcapacity of colestipol and cholestyramine. About 98% of available niacin wasbound to colestipol, with 10 to 30% binding to cholestyramine [see Drug Interactions ( 7.2)].
Niacin administered to mice for a lifetime as a1% solution in drinking water was not carcinogenic. The mice in this studyreceived approximately 6 to 8 times a human dose of 3,000 mg/day as determinedon a mg/m2 basis. Niacin was negative for mutagenicity in the Amestest. No studies on impairment of fertility have been performed. No studieshave been conducted with niacin extended-release regarding carcinogenesis, mutagenesis, or impairmentof fertility.
The role of LDL-C inatherogenesis is supported by pathological observations, clinical studies, andmany animal experiments. Observational epidemiological studies have clearlyestablished that high TC or LDL-C and low HDL-C are risk factors for CHD.Additionally, elevated levels of Lp(a) have been shown to be independentlyassociated with CHD risk.
Niacin's ability to reducemortality and the risk of definite, nonfatal myocardial infarction (MI) hasbeen assessed in long-term studies. The Coronary Drug Project, completed in1975, was designed to assess the safety and efficacy of niacin and otherlipid-altering drugs in men 30 to 64 years old with a history of MI. Over anobservation period of 5 years, niacin treatment was associated with astatistically significant reduction in nonfatal, recurrent MI. The incidence ofdefinite, nonfatal MI was 8.9% for the 1,119 patients randomized to nicotinicacid versus 12.2% for the 2,789 patients who received placebo (p<0.004). Total mortality was similarin the two groups at 5 years (24.4% with nicotinic acid versus 25.4% withplacebo; p=N.S. ). At the time of a15-year follow-up, there were 11% (69) fewer deaths in the niacin groupcompared to the placebo cohort (52% versus 58.2%; p=0.0004).
However, mortality at 15 years was not an original endpoint of the CoronaryDrug Project. In addition, patients had not received niacin for approximately 9years, andconfounding variables such as concomitant medication use and medical orsurgical treatments were not controlled.
The Cholesterol-LoweringAtherosclerosis Study (CLAS) was a randomized, placebo-controlled, angiographictrial testing combined colestipol and niacin therapy in 162 non-smoking maleswith previous coronary bypass surgery.
The primary, per-subject cardiacendpoint was global coronary artery change score. After 2 years, 61% ofpatients in the placebo cohort showed disease progression by global changescore (n=82), compared with only 38.8% of drug-treated subjects (n=80), whenboth native arteries and grafts were considered (p<0.005); disease regression also occurred more frequently inthe drug-treated group (16.2% versus 2.4%; p=0.002).In a follow-up to this trial in a subgroup of 103 patients treated for 4 years,again, significantly fewer patients in the drug-treated group demonstratedprogression than in the placebo cohort (48% versus 85%, respectively; p<0.0001).
The Familial AtherosclerosisTreatment Study (FATS) in 146 men ages 62 and younger with Apo B levels >=125mg/dL, established coronary artery disease, and family histories of vasculardisease, assessed change in severity of disease in the proximal coronaryarteries by quantitative arteriography. Patients were given dietary counselingand randomized to treatment with either conventional therapy with doubleplacebo (or placebo plus colestipol if the LDL-C was elevated); lovastatin pluscolestipol; or niacin plus colestipol. In the conventional therapy group, 46%of patients had disease progression (and no regression) in at least one of nineproximal coronary segments; regression was the only change in 11%. In contrast,progression (as the only change) was seen in only 25% in the niacin pluscolestipol group, while regression was observed in 39%. Though not an originalendpoint of the trial, clinical events (death, MI, or revascularization forworsening angina) occurred in 10 of 52 patients who received conventionaltherapy, compared with 2 of 48 who received niacin plus colestipol.
The Harvard Atherosclerosis Reversibility Project(HARP) was a randomized placebo-controlled, 2.5-year study of the effect of astepped-care antihyperlipidemic drug regimen on 91 patients (80 men and 11women) with CHD and average baseline TC levels less than 250 mg/dL and ratiosof TC to HDL-C greater than 4.
Drug treatment consisted of anHMG-CoA reductase inhibitor administered alone as initial therapy followed byaddition of varying dosages of either a slow-release nicotinic acid,cholestyramine, or gemfibrozil. Addition of nicotinic acid to the HMG-CoAreductase inhibitor resulted in further statistically significant meanreductions in TC, LDL-C, and TG, as well as a further increase in HDL-C in amajority of patients (40 of 44 patients). The ratios of TC to HDL-C and LDL-Cto HDL-C were also significantly reduced by this combination drug regimen [see Warnings and Precautions (5.2 )].
Placebo-ControlledClinical Studies in Patients with Primary Hyperlipidemia and MixedDyslipidemia: Intwo randomized, double-blind, parallel, multi-center, placebo-controlledtrials, niacin extended-release tablets dosed at 1000 mg, 1500 mg or 2000 mg daily at bedtime witha low-fat snack for 16 weeks (including 4 weeks of dose escalation) favorablyaltered lipid profiles compared to placebo (Table 3). Women appeared to have agreater response than men at each niacin extended-release tablets dose level(see Gender Effect, below).
| Mean Percent Change from Baseline to Week 16 | |||||||||
| Treatment | n | TC | LDL-C | HDL-C | TC/HDL-C | TG | Lp(a) | Apo B | Apo A-I |
| Niacin extended-release tablets 1000 mg at bedtime | 41 | -3 | -5 | +18 | -17 | -21 | -13 | -6 | +9 |
| Niacin extended-release tablets 2000 mg at bedtime | 41 | -10 | -14 | +22 | -25 | -28 | -27 | -16 | +8 |
| Placebo | 40 | 0 | -1 | +4 | -3 | 0 | 0 | +1 | +3 |
| Niacin extended-release tablets 1500 mg at bedtime | 76 | -8 | -12 | +20 | -20 | -13 | -15 | -12 | +8 |
| Placebo | 73 | +2 | +1 | +2 | +1 | +12 | +2 | +1 | +2 |
| n = number of patients at baseline; | |||||||||
In a double-blind, multi-center,forced dose-escalation study, monthly 500 mg increases in niacinextended-release tablets dose resulted in incremental reductions ofapproximately 5% in LDL-C and Apo B levels in the daily dose range of 500 mgthrough 2000 mg (Table 4). Women again tended to have a greater response to niacinextended-release tablets than men (see GenderEffect, below).
| Mean Percent Change from Baseline | |||||||||
| Treatment | n | TC | LDL-C | HDL-C | TC/HDL-C | TG | Lp(a) | Apo B | Apo A-I |
| Placebo | 44 | -2 | -1 | +5 | -7 | -6 | -5 | -2 | +4 |
| Niacin extended-release tablets | 87 | ||||||||
| 500 mg at bedtime | -2 | -3 | +10 | -10 | -5 | -3 | -2 | +5 | |
| 1000 mg at bedtime | -5 | -9 | +15 | -17 | -11 | -12 | -7 | +8 | |
| 1500 mg at bedtime | -11 | -14 | +22 | -26 | -28 | -20 | -15 | +10 | |
| 2000 mg at bedtime | -12 | -17 | +26 | -29 | -35 | -24 | -16 | +12 | |
| n = number of patients enrolled; | |||||||||
Pooled results for major lipidsfrom these three placebo-controlled studies are shown below (Table 5).
| Mean Baseline and Median Percent Change from Baseline (25 th , 75 th Percentiles) | ||||
| Niacin Extended-Release Tablets Dose | n | LDL-C | HDL-C | TG |
| 1000 mg at bedtime | 104 | |||
| Baseline (mg/dL) | 218 | 45 | 172 | |
| Percent Change | -7 (-15, 0) | +14 (+7, +23) | -16 (-34, +3) | |
| 1500 mg at bedtime | 120 | |||
| Baseline (mg/dL) | 212 | 46 | 171 | |
| Percent Change | -13 (-21, -4) | +19 (+9, +31) | -25 (-45, -2) | |
| 2000 mg at bedtime | 85 | |||
| Baseline (mg/dL) | 220 | 44 | 160 | |
| Percent Change | -16 (-26, -7) | +22 (+15, +34) | -38 (-52, -14) | |
GenderEffect:
Combined data from the threeplacebo-controlled niacin extended-release tablets studies in patients withprimary hyperlipidemia and mixed dyslipidemia suggest that, at each niacinextended-release tablets dose level studied, changes in lipid concentrationsare greater for women than for men (Table 6).
| Niacin Extended-Release Tablets | Mean Percent Change from Baseline | ||||||||
| n | LDL-C | HDL-C | TG | Apo B | |||||
| Dose | (M/F) | M | F | M | F | M | F | M | F |
| 500 mg at bedtime | 50/37 | -2 | -5 | +11 | +8 | -3 | -9 | -1 | -5 |
| 1000 mg at bedtime | 76/52 | -6 | -11 | +14 | +20 | -10 | -20 | -5 | -10 |
| 1500 mg at bedtime | 104/59 | -12 | -16 | +19 | +24 | -17 | -28 | -13 | -15 |
| 2000 mg at bedtime | 75/53 | -15 | -18 | +23 | +26 | -30 | -36 | -16 | -16 |
| n = number of male/female patients enrolled. | |||||||||
OtherPatient Populations:
In a double-blind, multi-center,19-week study the lipid-altering effects of niacin extended-release tablets(forced titration to 2000 mg at bedtime) were compared to baseline in patientswhose primary lipid abnormality was a low level of HDL-C (HDL-C <=40 mg/dL, TG<=400 mg/dL, and LDL-C <=160, or <130 mg/dL in the presence of CHD).Results are shown below (Table 7).
| Mean Baseline and Mean Percent Change from Baseline | ||||||||||
| n | TC | LDL-C | HDL-C | TC/HDL-C | TG | Lp(a) | Apo B | Apo A-I | Lp A-I | |
| Baseline (mg/dL) | 88 | 190 | 120 | 31 | 6 | 194 | 8 | 106 | 105 | 32 |
| Week 19 (% Change) | 71 | -3 | 0 | +26 | -22 | -30 | -20 | -9 | +11 | +20 |
| n = number of patients | ||||||||||
At niacin extended-releasetablets 2000 mg/day, median changes from baseline (25th, 75thpercentiles) for LDL-C, HDL-C, and TG were -3% (-14, +12%), +27% (+13, +38%),and -33% (-50, -19%), respectively.
Combination niacin extended-release andLovastatin Study: In a multi-center, randomized, double-blind, parallel,28-week study, a combination tablet of niacin extended-release andlovastatin was compared to each individual component in patients with Type IIaand IIb hyperlipidemia. Using a forced dose-escalation study design, patientsreceived each dose for at least 4 weeks. Patients randomized to treatmentwith the combination tablet of niacin extended-release andlovastatin initially received 500 mg/20 mg (expressed as mg of niacin/mg oflovastatin) once daily before bedtime. The dose was increased by 500 mg at4-week intervals (based on the niacin extended-release component)to a maximum dose of 1000 mg/20 mg in one-half of the patients and 2000 mg/40mg in the other half. The niacin extended-release monotherapygroup underwent a similar titration from 500 mg to 2000 mg. The patientsrandomized to lovastatin monotherapy received 20 mg for 12 weeks titrated to 40mg for up to 16 weeks. Up to a third of the patients randomized to thecombination tablet of niacin extended-release andlovastatin or niacin extended-release monotherapydiscontinued prior to Week 28. Results from this study showed that combinationtherapy decreased LDL-C, TG and Lp(a), and increased HDL-C in a dose-dependentfashion (Tables 8, 9, 10, and 11). Results from this study for LDL-C meanpercent change from baseline (the primary efficacy variable) showed that:
1. LDL-lowering with the combination tablet of niacin extended-release and lovastatin was significantly greater than that achievedwith lovastatin 40 mg only after 28 weeks of titration to a dose of 2000 mg/40mg (p<0.0001)
2. The combination tablet of niacin extended-release and lovastatin at doses of 1000 mg/20 mg or higher achievedgreater LDL-lowering than niacin extended-release (p<0.0001)
The LDL-C results are summarizedin Table 8.
| Week | Combination Tablet of Niacin Extended - Release and Lovastatin | Niacin Extended - Release | Lovastatin | ||||||
| n | Dose (mg/mg) | LDL | n | Dose (mg) | LDL | n | Dose (mg) | LDL | |
| Baseline | 57 | - | 190.9 mg/dL | 61 | - | 189.7 mg/dL | 61 | - | 185.6 mg/dL |
| 12 | 47 | 1000/20 | -30% | 46 | 1000 | -3% | 56 | 20 | -29% |
| 16 | 45 | 1000/40 | -36% | 44 | 1000 | -6% | 56 | 40 | -31% |
| 20 | 42 | 1500/40 | -37% | 43 | 1500 | -12% | 54 | 40 | -34% |
| 28 | 42 | 2000/40 | -42% | 41 | 2000 | -14% | 53 | 40 | -32% |
Combination therapy achievedsignificantly greater HDL-raising compared to lovastatin and niacin extended-release monotherapyat all doses (Table 9).
| Week | Combination Tablet of Niacin Extended - Release and Lovastatin | Niacin Extended - Release | Lovastatin | ||||||
| n | Dose (mg/mg) | HDL | n | Dose (mg) | HDL | n | Dose (mg) | HDL | |
| Baseline | 57 | - | 45 mg/dL | 61 | - | 47 mg/dL | 61 | - | 43 mg/dL |
| 12 | 47 | 1000/20 | +20% | 46 | 1000 | +14% | 56 | 20 | +3% |
| 16 | 45 | 1000/40 | +20% | 44 | 1000 | +15% | 56 | 40 | +5% |
| 20 | 42 | 1500/40 | +27% | 43 | 1500 | +22% | 54 | 40 | +6% |
| 28 | 42 | 2000/40 | +30% | 41 | 2000 | +24% | 53 | 40 | +6% |
In addition, combination therapyachieved significantly greater TG lowering at doses of 1000 mg/20mg or greatercompared to lovastatin and niacin extended-release monotherapy(Table 10).
| Week | Combination Tablet of Niacin Extended - Release and Lovastatin | Niacin Extended - Release | Lovastatin | ||||||
| n | Dose (mg/mg) | TG | n | Dose (mg) | TG | n | Dose (mg) | TG | |
| Baseline | 57 | - | 174 mg/dL | 61 | - | 186 mg/dL | 61 | - | 171 mg/dL |
| 12 | 47 | 1000/20 | -32% | 46 | 1000 | -22% | 56 | 20 | -20% |
| 16 | 45 | 1000/40 | -39% | 44 | 1000 | -23% | 56 | 40 | -17% |
| 20 | 42 | 1500/40 | -44% | 43 | 1500 | -31% | 54 | 40 | -21% |
| 28 | 42 | 2000/40 | -44% | 41 | 2000 | -31% | 53 | 40 | -20% |
The Lp(a)-lowering effects ofcombination therapy and niacin extended-release monotherapywere similar, and both were superior to lovastatin (Table 11). The independenteffect of lowering Lp(a) with niacin extended-release orcombination therapy on the risk of coronary and cardiovascular morbidity andmortality has not been determined.
| Week | Combination Tablet of Niacin Extended - Release and Lovastatin | Niacin Extended - Release | Lovastatin | ||||||
| n | Dose (mg/mg) | Lp(a) | n | Dose (mg) | Lp(a) | n | Dose (mg) | Lp(a) | |
| Baseline | 57 | - | 34 mg/dL | 61 | - | 41 mg/dL | 60 | - | 42 mg/dL |
| 12 | 47 | 1000/20 | -9% | 46 | 1000 | -8% | 55 | 20 | +8% |
| 16 | 45 | 1000/40 | -9% | 44 | 1000 | -12% | 55 | 40 | +8% |
| 20 | 42 | 1500/40 | -17% | 43 | 1500 | -22% | 53 | 40 | +6% |
| 28 | 42 | 2000/40 | -22% | 41 | 2000 | -32% | 52 | 40 | 0% |
In a double-blind, randomized,multicenter, multi-national, active-controlled, 24-week study, the lipideffects of a combination tablet of niacin extended-release andsimvastatin were compared to simvastatin 20 mg and 80 mg in 641 patients withtype II hyperlipidemia or mixed dyslipidemia. Following a lipid qualificationphase, patients were eligible to enter one of two treatment groups. In Group A,patients on simvastatin 20 mg monotherapy, with elevated non-HDL levels andLDL-C levels at goal per the NCEP guidelines, were randomized to one of threetreatment arms: combination tablet of niacin extended-release andsimvastatin 1000/20 mg, combination tablet of niacin extended-release andsimvastatin 2000/20 mg, or simvastatin 20 mg. In Group B, patients onsimvastatin 40 mg monotherapy, with elevated non-HDL levels per the NCEPguidelines regardless of attainment of LDL-C goals, were randomized to one ofthree treatment arms: combination tablet of niacin extended-release andsimvastatin 1000/40 mg, combination tablet of niacin extended-release andsimvastatin 2000/40 mg, or simvastatin 80 mg. Therapy was initiated at the 500mg dose of combination tablet of niacin extended-release andsimvastatin and increased by 500 mg every four weeks. Thus patients weretitrated to the 1000 mg dose of combination tablet of niacin extended-release andsimvastatin after four weeks and to the 2000 mg dose of combination tablet ofniacin extended-release andsimvastatin after 12 weeks. All patients randomized to simvastatin monotherapyreceived 50 mg immediate-release niacin daily in an attempt to keep the studyfrom becoming unblinded due to flushing in the combination tablet of niacin extended-release andsimvastatin groups. Patients were instructed to take one 325 mg aspirin or 200mg ibuprofen 30 minutes prior to taking the double-blind medication to helpminimize flushing effects.
In Group A, the primary efficacyanalysis was a comparison of the mean percent change in non-HDL levels betweenthe combination tablet of niacin extended-release andsimvastatin 2000/20 mg and simvastatin 20 mg groups, and if statisticallysignificant, then a comparison was conducted between the combination tablet ofniacin extended-release andsimvastatin 1000/20 mg and simvastatin 20 mg groups. In Group B, the primaryefficacy analysis was a determination of whether the mean percent change innon-HDL in the combination tablet of niacin extended-release andsimvastatin 2000/40 mg group was non-inferior to the mean percent change in thesimvastatin 80 mg group, and if so, whether the mean percent change in non-HDLin the combination tablet of niacin extended-release andsimvastatin 1000/40 mg group was non-inferior to the mean percent change in thesimvastatin 80 mg group.
In Group A, the non-HDL-Clowering with combination tablet of niacin extended-release andsimvastatin 2000/20 and combination tablet of niacin extended-release andsimvastatin 1000/20 was statistically significantly greater than that achievedwith simvastatin 20 mg after 24 weeks (p<0.05; Table 12). The completion rate after 24 weeks was 72% for the combinationtablet of niacin extended-release andsimvastatin arms and 88% for the simvastatin 20 mg arm. In Group B, thenon-HDL-C lowering with combination tablet of niacin extended-release andsimvastatin 2000/40 and combination tablet of niacin extended-release andsimvastatin 1000/40 was non-inferior to that achieved with simvastatin 80 mgafter 24 weeks (Table 13). The completion rate after 24 weeks was 78% for thecombination tablet of niacin extended-release andsimvastatin arms and 80% for the simvastatin 80 mg arm.
The combination tablet of niacin extended-release andsimvastatin was not superior to simvastatin in lowering LDL-C in either Group Aor Group B. However, the combination tablet of niacin extended-release andsimvastatin was superior to simvastatin in both groups in lowering TG andraising HDL (Tables 14 and 15).
| Group A | Combination Tablet of Niacin Extended - Release and Simvastatin 2000/20 | Combination Tablet of Niacin Extended - Release and Simvastatin 1000/20 | Simvastatin 20 | ||||||
| Week | n | Dose (mg/mg) | Non-HDL | n | Dose (mg/mg) | Non-HDL | n | Dose (mg/mg) | Non-HDL |
| 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% |
| Dropouts by week 24: | 28.6% | 27.8% | 11.8% | ||||||
| Group B | Combination Tablet of Niacin Extended - Release and Simvastatin 2000/40 | Combination Tablet of Niacin Extended - Release and Simvastatin 1000/40 | Simvastatin 80 | ||||||
| Week | n | Dose (mg/mg) | Non- HDL | n | Dose (mg/mg) | Non- HDL | n | Dose (mg/mg) | Non-HDL |
| Baseline | 98 | - | 144.4 mg/dL | 111 | - | 141.2 mg/dL | 113 | - | 134.5 mg/dL |
| 4 | 96 | 500/40 | -6% | 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% | 82 | 1000/40 | -6.7% | 90 | 80 | -6% |
| Dropouts by week 24: | 18.4% | 26.1% | 20.4% | ||||||
| Treatment Group A | ||||||
| TREATMENT | N | LDL-C | Total-C | HDL-C | TG | Apo B |
| Baseline (mg/dL) | 266 | 120 | 207 | 43 | 209 | 102 |
| Simvastatin 20 mg | 102 | -6.7% | -4.5% | 7.8% | -15.3% | -5.6% |
| Combination Tablet of Niacin Extended-Release and Simvastatin 1000/20 | 108 | -11.9% | -8.8% | 20.7% | -26.5% | -13.2% |
| Combination Tablet of Niacin Extended-Release and Simvastatin 2000/20 | 56 | -14.3% | -11.1% | 29% | -38% | -18.5% |
| Treatment Group B | ||||||
| TREATMENT | N | LDL-C | Total-C | HDL-C | TG | Apo B |
| Baseline (mg/dL) | 322 | 108 | 187 | 47 | 145 | 93 |
| Simvastatin 80 mg | 113 | -11.4% | -6.2% | 0.1% | 0.3% | -7.5% |
| Combination Tablet of Niacin Extended-Release and Simvastatin 1000/40 | 111 | -7.1% | -3.1% | 15.4% | -22.8% | -7.7% |
| Combination Tablet of Niacin Extended-Release and Simvastatin 2000/40 | 98 | -5.1 | -1.6% | 24.4% | -31.8% | -10.5% |
Niacin extended-release tablets, USP are supplied as unscored, pink, film-coated, capsule-shaped tablets containing 500 mg, 750 mg or 1000 mg of niacin USP in an extended-release formulation. Tablets are debossed 'S' on one side and the tablet strength (500, 750 or 1000) on the other side.
Tablets are supplied as follows:
500 mg tablets:
Bottles of 30's with Child Resistant Cap.......................NDC 47335-539-83
Bottles of 90's with Child Resistant Cap.......................NDC 47335-539-81
Bottles of 100's with Child Resistant Cap.....................NDC 47335-539-88
Bottles of 100's with Non Child Resistant Cap............NDC 47335-539-08
Bottles of 1000's with Non Child Resistant Cap.........NDC 47335-539-18
750 mg tablets:
Bottles of 30's with Child Resistant Cap.......................NDC 47335-614-83
Bottles of 90's with Child Resistant Cap.......................NDC 47335-614-81
Bottles of 100's with Child Resistant Cap.....................NDC 47335-614-88
Bottles of 1000's with Non Child Resistant Cap.........NDC 47335-614-18
1000 mg tablets
Bottles of 30's with Child Resistant Cap.......................NDC 47335-613-83
Bottles of 90's with Child Resistant Cap.......................NDC 47335-613-81
Bottles of 100's with Child Resistant Cap.....................NDC 47335-613-88
Bottles of 100's with Non Child Resistant Cap............NDC 47335-613-08
Bottles of 1000's with Non Child Resistant Cap.........NDC 47335-613-18
Storage: Store at 20deg to 25degC (68deg to 77degF); excursions permitted between 15deg and 30degC (59deg and 86degF) [see USP Controlled Room Temperature].
Dispense in a tight container with child-resistant closure.
Patients should be advised toadhere to their National Cholesterol Education Program (NCEP) recommended diet,a regular exercise program, and periodic testing of a fasting lipid panel.
Patients should be advised to inform other healthcare professionals prescribinga new medication that they are taking niacin extended-release tablets.
The patient should be informed of the following:
Dosing Time
Niacin extended-release tabletsshould be taken at bedtime, after a low-fat snack. Administration on an emptystomach is not recommended.
Tablet Integrity
Niacin extended-release tablets shouldnot be broken, crushed or chewed, but should be swallowed whole.
DosingInterruption
If dosing is interrupted for anylength of time, their physician should be contacted prior to restartingtherapy; re-titration is recommended.
Muscle Pain
Notify theirphysician of any unexplained muscle pain, tenderness, or weakness promptly.They should discuss all medication, both prescription and over the counter,with their physician.
Flushing Flushing (warmth, redness, itching and/or tingling of the skin) is a commonside effect of niacin therapy that may subside after several weeks ofconsistent niacin extended-release tablets use. Flushing may vary in severityand is more likely to occur with initiation of therapy, or during doseincreases. By dosing at bedtime, flushing will most likely occur during sleep.However, if awakened by flushing at night, the patient should get up slowly,especially if feeling dizzy, feeling faint, or taking blood pressuremedications. Advise patients of the symptoms of flushing and how they differfrom the symptoms of a myocardial infarction.
Use of Aspirin Medication
Taking aspirin (up to therecommended dose of 325 mg) approximately 30 minutes before dosing can minimizeflushing.
Diet Avoid ingestion of alcohol, hot beverages and spicy foods around the timeof taking niacin extended-release tablets to minimize flushing.
Supplements
Notify their physician if theyare taking vitamins or other nutritional supplements containing niacin or nicotinamide.
Dizziness Notify their physician if symptoms of dizziness occur.
Diabetics
If diabetic, to notify theirphysician of changes in blood glucose.
Pregnancy Discuss futurepregnancy plans with your patients, and discuss when to stop niacin extended-releasetablets if they are trying to conceive. Patients should be advised that if theybecome pregnant, they should stop taking niacin extended-release tablets andcall their healthcare professional.
Breastfeeding Women who are breastfeeding should be advised to not use niacinextended-release tablets. Patients, who have a lipid disorder and arebreastfeeding, should be advised to discuss the options with their healthcareprofessional.
Niacin (nahy-uh-sin)
Extended-Release Tablets, USP
Read this information carefully before you start taking niacin extended-release tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.
What are niacin extended-release tablets?
Niacin extended-release tablets are prescription medicines used with diet and exercise to increase the good cholesterol (HDL) and lower the bad cholesterol (LDL) and fats (triglycerides) in your blood.
Niacin extended-release tablets can be used by itself or with other cholesterol-lowering medicines
Niacin extended-release tablets are also used to lower the risk of heart attack in people who have had a heart attack and have high cholesterol.
In people with coronary artery disease and high cholesterol, niacin extended-release tablets, when used with a bile acid-binding resin (another cholesterol medicine) can slow down or lessen the build-up of plaque (fatty deposits) in your arteries
In people with heart problems and well-controlled cholesterol, taking niacin extended-release tablets with another cholesterol-lowering medicine (simvastatin) has not been shown to reduce heart attacks or strokes more than taking simvastatin alone.
It is not known if niacin extended-release tablets are safe and effective in children 16 years of age and under.
Who should not take niacin extended-release tablets?
Do not take niacin extended-release tablets if you have:
liver problems
a stomach ulcer
bleeding problems
an allergy to niacin or any of the ingredients in niacin extended-release tablets. See the end of this leaflet for a complete list of ingredients in niacin extended-release tablets.
What should I tell my doctor before taking niacin extended-release tablets?
Before you take niacin extended-release tablets, tell your doctor, if you:
have diabetes. Tell your doctor if your blood sugar levels change after you take niacin extended-release tablets.
have gout
have kidney problems
are pregnant or plan to become pregnant. It is not known if niacin extended-release tablets will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant while taking niacin extended-release tablets.
are breastfeeding or plan to breastfeed. Niacin can pass into your breast milk. You and your doctor should decide if you will take niacin extended-release tablets or breastfeed. You should not do both. Talk to your doctor about the best way to feed your baby if you take niacin extended-release tablets.
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements or other nutritional supplements containing niacin or nicotinamide. Niacin extended-release tablets and other medicines may affect each other causing side effects. Niacin extended-release tablets may affect the way other medicines work, and other medicines may affect how niacin extended-release tablets work.
Especially tell your doctor if you take:
other medicines to lower cholesterol or triglycerides
aspirin
blood pressure medicines
blood thinner medicines
large amounts of alcohol
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I take niacin extended-release tablets?
Take niacin extended-release tablets exactly as your doctor tells you to take it.
Take niacin extended-release tablets whole. Do not break, crush or chew niacin extended-release tablets before swallowing.
Take niacin extended-release tablets 1 time a day at bedtime after a low-fat snack. Niacin extended-release tablets should not be taken on an empty stomach.
All forms of niacin are not the same as niacin extended-release tablets. Do not switch between forms of niacin without first talking to your doctor as severe liver damage can occur.
Do not change your dose or stop taking niacin extended-release tablets unless your doctor tells you to.
If you need to stop taking niacin extended-release tablets, call your doctor before you start taking niacin extended-release tablets again. Your doctor may need to lower your dose of niacin extended-release tablets.
If you forget to take a dose of niacin extended-release tablets, take it as soon as you remember.
If you take too many niacin extended-release tablets, call your doctor right away.
Medicines used to lower your cholesterol called bile acid resins, such as colestipol and cholestyramine, should not be taken at the same time of day as niacin extended-release tablets. You should take niacin extended-release tablets and the bile acid resin medicine at least 4 to 6 hours apart.
Your doctor may do blood tests before you start taking niacin extended-release tablets and during your treatment. You should see your doctor regularly to check your cholesterol and triglyceride levels and to check for side effects.
What are the possible side effects of niacin extended-release tablets?
Niacin extended-release tablets may cause serious side effects, including:
severe liver problems. Signs of liver problems include: increased tiredness dark colored urine (tea-colored) loss of appetite light colored stools nausea right upper stomach (abdomen) pain yellowing of your skin or whites of your eye itchy skin
increased tiredness
dark colored urine (tea-colored)
loss of appetite
light colored stools
nausea
right upper stomach (abdomen) pain
yellowing of your skin or whites of your eye
itchy skin
unexplained muscle pain, tenderness or weakness
high blood sugar level (glucose)
Call your doctor right away if you have any of the side effects listed above.
The most common side effects of niacin extended-release tablets include:
flushing
diarrhea
nausea
vomiting
increased cough
rash
Flushing is the most common side effect of niacin extended-release tablets. Flushing happens when tiny blood vessels near the surface of the skin (especially on the face, neck, chest and/or back) open wider. Symptoms of flushing may include any or all of the following:
warmth
redness
itching
tingling of the skin
Flushing does not always happen. If it does, it is usually within 2 to 4 hours after taking a dose of niacin extended-release tablets. Flushing may last for a few hours. Flushing is more likely to happen when you first start taking niacin extended-release tablets or when your dose of niacin extended-release tablets is increased. Flushing may get better after several weeks.
If you wake up at night because of flushing, get up slowly, especially if you:
feel dizzy or faint
take blood pressure medicines
To lower your chance of flushing:
Ask your doctor if you can take aspirin to help lower the flushing side effect from niacin extended-release tablets. You can take aspirin (up to the recommended dose of 325 mg) about 30 minutes before you take niacin extended-release tablets to help lower the flushing side effect.
Do not drink hot beverages (including coffee), alcohol, or eat spicy foods around the time you take niacin extended-release tablets.
Take niacin extended-release tablets with a low-fat snack to lessen upset stomach.
People with high cholesterol and heart disease are at risk for a heart attack. Symptoms of a heart attack may be different from a flushing reaction from niacin extended-release tablets. The following may be symptoms of a heart attack due to heart disease and not a flushing reaction:
chest pain
pain in other areas of your upper body such as one or both arms, back, neck, jaw or stomach
shortness of breath
sweating
nausea
lightheadedness
The chest pain you have with a heart attack may feel like uncomfortable pressure, squeezing, fullness or pain that lasts more than a few minutes, or that goes away and comes back. Heart attacks may be sudden and intense, but often start slowly, with mild pain or discomfort.
Call your doctor right away if you have any symptoms of a heart attack.
Tell your doctor if you have any side effect that bothers you or does not go away.
These are not all the possible side effects of niacin extended-release tablets. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store niacin extended-release tablets?
Store at 20deg to 25degC (68deg to 77degF); excursions permitted between 15deg and 30degC (59deg and 86degF).
Keep niacin extended-release tablets and all medicines out of the reach of children.
General information about the safe and effective use of niacin extended-release tablets
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use niacin extended-release tablets for a condition for which it was not prescribed. Do not give niacin extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about niacin extended-release tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about niacin extended-release tablets that is written for health professionals.
For more information, call 1-800-818-4555.
What are the ingredients in niacin extended-release tablets?
Active ingredient:
niacin
Inactive Ingredients:
hypromellose, hydrogenated vegetable oil Type I, glyceryl behenate, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol-partially hydrolyzed, titanium dioxide, polyethylene glycol, talc, iron oxide red and iron oxide yellow.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Distributed by:
Caraco Pharmaceutical Laboratories Limited
1150 Elijah McCoy Drive, Detroit, MI 48202
Manufactured by:
Sun Pharma Laboratories Limited
Survey No. 259/15,
Dadra-396 191, (U.T. of D & NH), India.
PGPI0180A
ISS. 05/2014
NDC 47335-539-83Niacin Extended-release Tablets, USP500 mgRx only30 TabletsSUN PHARMAPHARMACIST: Dispense with patient package insert.
NDC 47335-614-83Niacin Extended-release Tablets, USP750 mgRx only30 TabletsSUN PHARMAPHARMACIST: Dispense with patient package insert.
NDC 47335-613-83Niacin Extended-release Tablets, USP1000 mgRx only30 TabletsSUN PHARMAPHARMACIST: Dispense with patient package insert.