7 • 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 tablet administration.
( 7.2 ) 7.1 Statins Caution should be used when prescribing niacin (≥1 gm/day) with statins as these drugs can increase risk of myopathy/rhabdomyolysis [see Warnings and Precautions ( 5 ) and Clinical Pharmacology ( 12.3 )] .
7.2 Bile Acid Sequestrants An in vitro study results suggest that the bile acid-binding resins have high niacin binding capacity.
Therefore, 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of niacin extended-release tablets [see Clinical Pharmacology ( 12.3 )] .
7.3 Aspirin Concomitant aspirin may decrease the metabolic clearance of nicotinic acid.
The clinical relevance of this finding is unclear.
7.4 Antihypertensive Therapy Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension.
7.5 Other 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 tablets.
7.6 Laboratory Test Interactions Niacin may produce false elevations in some fluorometric determinations of plasma or urinary catecholamines.
Niacin may also give false-positive reactions with cupric sulfate solution (Benedict’s reagent) in urine glucose tests.
10 Supportive measures should be undertaken in the event of an overdose.
11 Niacin Extended-Release Tablets USP, contain niacin, USP, which at therapeutic doses is an antihyperlipidemic agent.
Niacin, USP (nicotinic acid, or 3-pyridinecarboxylic acid) is a white, crystalline powder, very soluble in water, with the following structural formula: Niacin Extended-Release Tablets USP are white to off-white, capsule-shaped, unscored, biconvex, debossed 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 following inactive ingredients: hypromellose, povidone, and stearic acid.
14 14.1 Niacin Clinical Studies Niacin’s ability to reduce mortality and the risk of definite, nonfatal myocardial infarction (MI) has been assessed in long-term studies.
The Coronary Drug Project, completed in 1975, was designed to assess the safety and efficacy of niacin and other lipid-altering drugs in men 30 to 64 years old with a history of MI.
Over an observation period of 5 years, niacin treatment was associated with a statistically significant reduction in nonfatal, recurrent MI.
The incidence of definite, nonfatal MI was 8.9% for the 1,119 patients randomized to nicotinic acid versus 12.2% for the 2,789 patients who received placebo ( p < 0.004).
Total mortality was similar in the two groups at 5 years (24.4% with nicotinic acid versus 25.4% with placebo; p = N.S.).
At the time of a 15-year follow-up, there were 11% (69) fewer deaths in the niacin group compared to the placebo cohort (52% versus 58.2%; p = 0.0004).
However, mortality at 15 years was not an original endpoint of the Coronary Drug Project.
In addition, patients had not received niacin for approximately 9 years, and confounding variables such as concomitant medication use and medical or surgical treatments were not controlled.
The Cholesterol-Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled, angiographic trial testing combined colestipol and niacin therapy in 162 non-smoking males with previous coronary bypass surgery.
The primary, per-subject cardiac endpoint was global coronary artery change score.
After 2 years, 61% of patients in the placebo cohort showed disease progression by global change score (n = 82), compared with only 38.8% of drug-treated subjects (n = 80), when both native arteries and grafts were considered ( p < 0.005); disease regression also occurred more frequently in the 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 demonstrated progression than in the placebo cohort (48% versus 85%, respectively; p < 0.0001).
The Familial Atherosclerosis Treatment Study (FATS) in 146 men ages 62 and younger with Apo B levels ≥ 125 mg/dL, established coronary artery disease, and family histories of vascular disease, assessed change in severity of disease in the proximal coronary arteries by quantitative arteriography.
Patients were given dietary counseling and randomized to treatment with either conventional therapy with double placebo (or placebo plus colestipol if the LDL-C was elevated); lovastatin plus colestipol; or niacin plus colestipol.
In the conventional therapy group, 46% of patients had disease progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11%.
In contrast, progression (as the only change) was seen in only 25% in the niacin plus colestipol group, while regression was observed in 39%.
Though not an original endpoint of the trial, clinical events (death, MI, or revascularization for worsening angina) occurred in 10 of 52 patients who received conventional therapy, compared with 2 of 48 who received niacin plus colestipol.
14.2 Niacin Extended-Release Tablet Clinical Studies Placebo-Controlled Clinical Studies in Patients with Primary Hyperlipidemia and Mixed Dyslipidemia: In two randomized, double-blind, parallel, multi-center, placebo-controlled trials, niacin extended-release tablets dosed at 1000, 1500 or 2000 mg daily at bedtime with a low-fat snack for 16 weeks (including 4 weeks of dose escalation) favorably altered lipid profiles compared to placebo ( Table 3 ).
Women appeared to have a greater response than men at each niacin extended-release tablet dose level (see Gender Effect , below).
Lipid Response to Niacin Extended-Release Tablet Therapy Mean Percent Change from Baseline to Week 16 Mean percent change from baseline for all niacin extended-release tablet doses was significantly different ( p < 0.05) from placebo.
Treatment n TC LDL-C HDL-C TG Apo B Niacin Extended-Release Tablets 1000 mg at bedtime 41 -3 -5 +18 -21 -6 Niacin Extended-Release Tablets 2000 mg at bedtime 41 -10 -14 +22 -28 -16 Placebo 40 0 -1 +4 0 +1 Niacin Extended-Release Tablets 1500 mg at bedtime 76 -8 -12 +20 -13 -12 Placebo 73 +2 +1 +2 +12 +1 n = number of patients at baseline.
In a double-blind, multi-center, forced dose-escalation study, monthly 500 mg increases in niacin extended-release tablet dose resulted in incremental reductions of approximately 5% in LDL-C and Apo B levels in the daily dose range of 500 mg through 2000 mg ( Table 4 ).
Women again tended to have a greater response to niacin extended-release tablets than men (see Gender Effect , below).
Lipid Response in Dose-Escalation Study Mean Percent Change from Baseline For all niacin extended-release tablet doses except 500 mg, mean percent change from baseline was significantly different ( p < 0.05) from placebo for all lipid parameters shown.
Treatment n TC LDL-C HDL-C TG Apo B Placebo Placebo data shown are after 24 weeks of placebo treatment.
44 -2 -1 +5 -6 -2 Niacin Extended-Release Tablets 87 500 mg at bedtime -2 -3 +10 -5 -2 1000 mg at bedtime -5 -9 +15 -11 -7 1500 mg at bedtime -11 -14 +22 -28 -15 2000 mg at bedtime -12 -17 +26 -35 -16 n = number of patients enrolled.
Pooled results for major lipids from these three placebo-controlled studies are shown below ( Table 5 ).
Selected Lipid Response to Niacin Extended-Release Tablets in Placebo-Controlled Clinical Studies Represents pooled analyses of results; minimum duration on therapy at each dose was 4 weeks.
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) Gender Effect: Combined data from the three placebo-controlled niacin extended-release tablet studies in patients with primary hyperlipidemia and mixed dyslipidemia suggest that, at each niacin extended-release tablet dose level studied, changes in lipid concentrations are greater for women than for men ( Table 6 ).
Effect of Gender on Niacin Extended-Release Tablet Dose Response Mean Percent Change from Baseline Niacin Extended-Release Tablets 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 Percent change significantly different between genders ( p < 0.05).
-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.
Other Patient 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 patients whose 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 ).
Lipid Response to Niacin Extended-Release Tablets in Patients with Low HDL-C Mean Baseline and Mean Percent Change from Baseline Mean percent change from baseline was significantly different ( p < 0.05) for all lipid parameters shown except LDL-C.
n TC LDL-C HDL-C TG Apo B n = 72 at baseline and 69 at week 19.
Baseline (mg/dL) 88 190 120 31 194 106 Week 19 (% Change) 71 -3 0 +26 -30 -9 n = number of patients.
At niacin extended-release 2000 mg/day, median changes from baseline (25th, 75th percentiles) for LDL-C, HDL-C, and TG were -3% (-14, +12%), +27% (+13, +38%), and -33% (-50, -19%), respectively.
16 /STORAGE AND HANDLING Niacin Extended-Release Tablets USP are supplied as follows: 500 mg: White to off-white, capsule-shaped, unscored, biconvex tablet.
Debossed with stylized b 212 on one side and 500 on the other side.
Available in bottles of 90 (NDC 0093-7392-98) and 180 (NDC 0093-7392-86) tablets.
750 mg: White to off-white, capsule-shaped, unscored, biconvex tablet.
Debossed with stylized b 213 on one side and 750 on the other side.
Available in bottles of 90 (NDC 0093-7393-98) and 180 (NDC 0093-7393-86) tablets.
1000 mg: White to off-white, capsule-shaped, unscored, biconvex tablet.
Debossed with stylized b 214 on one side and 1000 on the other side.
Available in bottles of 90 (NDC 0093-7394-98) and 180 (NDC 0093-7394-86) tablets.
Storage: Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
RECENT MAJOR CHANGES
Indications and Usage, Combination With a Statin – removal ( 1 ) 04/2015 Dosage and Administration, Combination With a Statin – removal ( 2 ) 04/2015
8.5 Geriatric Use Of 979 patients in clinical studies of niacin extended-release tablets, 21% of the patients were age 65 and over.
No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
DOSAGE FORMS AND STRENGTHS
3 • 500 mg white to off-white, capsule-shaped, unscored, biconvex, debossed tablets • 750 mg white to off-white, capsule-shaped, unscored, biconvex, debossed tablets • 1000 mg white to off-white, capsule-shaped, unscored, biconvex, debossed tablets Capsule-shaped, unscored, biconvex, debossed tablets for oral administration: 500 mg, 750 mg, and 1000 mg niacin extended-release.
( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The mechanism by which niacin alters lipid profiles has not been well defined.
It may involve several actions including partial inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity, which may increase the rate of chylomicron triglyceride removal from plasma.
Niacin decreases the rate of hepatic synthesis of VLDL and LDL, and does not appear to affect fecal excretion of fats, sterols, or bile acids.
INDICATIONS AND USAGE
1 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, USP 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.
In patients with a history of myocardial infarction and hyperlipidemia, niacin, USP is indicated to reduce the risk of recurrent nonfatal myocardial infarction.
In patients with a history of coronary artery disease (CAD) and hyperlipidemia, niacin, USP, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease.
Niacin Extended-Release Tablets USP in combination with a bile acid binding resin are indicated to reduce elevated TC and LDL-C levels in adult patients with primary hyperlipidemia.
Niacin, USP 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 Addition of Niacin Extended-Release Tablets USP did not reduce cardiovascular morbidity or mortality among patients treated with simvastatin in a large, randomized controlled trial (AIM-HIGH) [see Warnings and Precautions ( 5.1 ) ] .
Niacin Extended-Release Tablets USP contain extended-release niacin, USP (nicotinic acid), and is indicated: • To reduce elevated TC, LDL-C, Apo B and TG, and to increase HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia.( 1 ) • To reduce the risk of recurrent nonfatal myocardial infarction in patients with a history of myocardial infarction and hyperlipidemia.( 1 ) • In combination with a bile acid binding resin: ∘ Slows progression or promotes regression of atherosclerotic disease in patients with a history of coronary artery disease (CAD) and hyperlipidemia.
( 1 ) ∘ As an adjunct to diet to reduce elevated TC and LDL-C in adult patients with primary hyperlipidemia.
( 1 ) • To reduce TG in adult patients with severe hypertriglyceridemia.( 1 ) Limitations of Use: Addition of Niacin Extended-Release Tablets USP did not reduce cardiovascular morbidity or mortality among patients treated with simvastatin in a large, randomized controlled trial ( 5.1 ).
8.4 Pediatric Use Safety and effectiveness of niacin therapy in pediatric patients (≤ 16 years) have not been established.
8.1 Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with niacin or with niacin extended-release tablets.
It is also not known whether niacin at doses typically used for lipid disorders can cause fetal harm when administered to pregnant women or whether it can affect reproductive capacity.
If a woman receiving niacin for primary hyperlipidemia becomes pregnant, the drug should be discontinued.
If a woman being treated with niacin for hypertriglyceridemia conceives, the benefits and risks of continued therapy should be assessed on an individual basis.
8.3 Nursing Mothers 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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Niacin extended-release tablet preparations should not be substituted for equivalent doses of immediate-release (crystalline) niacin.
For patients switching from immediate-release niacin to niacin extended-release tablets, therapy with niacin extended-release tablets should be initiated with low doses (i.e., 500 mg at bedtime) and the niacin extended-release tablet dose should then be titrated to the desired therapeutic response [see Dosage and Administration ( 2 )] .
Caution should also be used when niacin extended-release tablets are used in patients with unstable angina or in the acute phase of an MI, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents.
Niacin is rapidly metabolized by the liver, and excreted through the kidneys.
Niacin extended-release tablets are contraindicated in patients with significant or unexplained hepatic impairment [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] and should be used with caution in patients with renal impairment.
Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during niacin extended-release tablet therapy.
• Severe hepatic toxicity has occurred in patients substituting sustained-release niacin for immediate-release niacin at equivalent doses.
( 5.3 ) • Myopathy has been reported in patients taking niacin extended-release tablets.
The risk for myopathy and rhabdomyolysis are increased among elderly patients; patients with diabetes, renal failure, or uncontrolled hypothyroidism; and patients being treated with a statin.
( 5.2 ) • Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur.
Monitor liver enzymes before and during treatment.
( 5.3 ) • Use with caution in patients with unstable angina or in the acute phase of an MI.
( 5 ) • Niacin extended-release tablets can increase serum glucose levels.
Glucose levels should be closely monitored in diabetic or potentially diabetic patients particularly during the first few months of use or dose adjustment.
( 5.4 ) 5.1 Mortality and Coronary Heart Disease Morbidity Niacin extended-release tablets have not been shown to reduce cardiovascular morbidity or mortality among patients already treated with a statin.
The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial was a randomized placebo-controlled trial of 3414 patients with stable, previously diagnosed cardiovascular disease.
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 to entering 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 80 mg/dL, and were randomized to receive niacin extended-release tablets 1500 to 2000 mg/day (n = 1718) or matching placebo (IR Niacin, 100 to 150 mg, n = 1696).
On-treatment lipid changes at two years for LDL-C were -12% for the simvastatin plus niacin extended-release tablets group and -5.5% for the simvastatin plus placebo group.
HDL-C increased by 25% to 42 mg/dL in the simvastatin plus niacin extended-release tablets 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 plus niacin extended-release tablets group and by 8.1% in the simvastatin plus placebo group.
The primary outcome was an ITT composite of the first study occurrence of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome or symptom-driven coronary or cerebral revascularization procedures.
The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy.
The primary outcome occurred in 282 patients in the simvastatin plus niacin extended-release tablets group (16.4%) and in 274 patients in the simvastatin 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 stroke reported, 27 (1.6%) in the simvastatin plus niacin extended-release tablets group and 15 (0.9%) in the simvastatin plus placebo group, a non-statistically significant result (HR 1.79, [95%CI = 0.95 to 3.36], p = 0.071).
The on-treatment ischemic stroke events were 19 for the simvastatin plus niacin extended-release tablets group and 15 for the simvastatin plus placebo group [see Adverse Reactions ( 6.1 )] .
5.2 Skeletal Muscle Cases of rhabdomyolysis have been associated with concomitant administration of lipid-altering doses (≥ 1 g/day) of niacin and statins.
Elderly patients and patients with diabetes, renal failure, or uncontrolled hypothyroidism are particularly at risk.
Monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration.
Periodic serum creatine phosphokinase (CPK) and potassium determinations should be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
5.3 Liver Dysfunction Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses.
Niacin extended-release tablets should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.
Active liver diseases or unexplained transaminase elevations are contraindications to the use of niacin extended-release tablets.
Niacin preparations have been associated with abnormal liver tests.
In three placebo-controlled clinical trials involving titration to final daily niacin extended-release tablet doses ranging from 500 to 3000 mg, 245 patients received niacin extended-release tablets for a mean duration of 17 weeks.
No patient with normal serum transaminase levels (AST, ALT) at baseline experienced elevations to more than 3 times the upper limit of normal (ULN) during treatment with niacin extended-release tablets.
In these studies, fewer than 1% (2/245) of niacin extended-release tablet patients discontinued due to transaminase elevations greater than 2 times the ULN.
Liver-related tests should be performed on all patients during therapy with niacin extended-release tablets.
Serum transaminase levels, including AST and ALT (SGOT and SGPT), should be monitored before treatment begins, every 6 to 12 weeks for the first year, and periodically thereafter (e.g., at approximately 6 month intervals).
Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently.
If the transaminase levels show evidence of progression, particularly if they rise to 3 times ULN and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise, the drug should be discontinued.
5.4 Laboratory Abnormalities Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose.
Frequent monitoring of blood glucose should be performed to ascertain that the drug is producing no adverse effects.
Diabetic patients may experience a dose-related increase in glucose intolerance.
Diabetic or potentially diabetic patients should be observed closely during treatment with niacin extended-release tablets, particularly during the first few months of use or dose adjustment; adjustment of diet and/or hypoglycemic therapy may be necessary.
Reduction in Platelet Count: Niacin extended-release tablets have been associated with small but statistically significant dose-related reductions in platelet count (mean of -11% with 2000 mg).
Caution should be observed when niacin extended-release tablets are administered concomitantly with anticoagulants; platelet counts should be monitored closely in such patients.
Increase in Prothrombin Time (PT): Niacin extended-release tablets have been associated with small but statistically significant increases in prothrombin time (mean of approximately +4%); accordingly, patients undergoing surgery should be carefully evaluated.
Caution should be observed when niacin extended-release tablets are administered concomitantly with anticoagulants; prothrombin time should be monitored closely in such patients.
Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy, therefore use with caution in patients predisposed to gout.
Decrease in Phosphorus: In placebo-controlled trials, niacin extended-release tablets have been associated with small but statistically significant, dose-related reductions in phosphorus levels (mean of -13% with 2000 mg).
Although these reductions were transient, phosphorus levels should be monitored periodically in patients at risk for hypophosphatemia.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION 17.1 Patient Counseling Patients should be advised to adhere 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 prescribing a new medication that they are taking niacin extended-release tablets.
The patient should be informed of the following: Dosing Time Niacin extended-release tablets should be taken at bedtime, after a low-fat snack.
Administration on an empty stomach is not recommended.
Tablet Integrity Niacin extended-release tablets should not be broken, crushed or chewed, but should be swallowed whole.
Dosing Interruption If dosing is interrupted for any length of time, their physician should be contacted prior to restarting therapy; re-titration is recommended.
Muscle Pain Notify their physician 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 common side effect of niacin therapy that may subside after several weeks of consistent niacin extended-release tablet use.
Flushing may vary in severity and is more likely to occur with initiation of therapy, or during dose increases.
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 pressure medications.
Advise patients of the symptoms of flushing and how they differ from the symptoms of a myocardial infarction.
Use of Aspirin Medication Taking aspirin (up to the recommended dose of 325 mg) approximately 30 minutes before dosing can minimize flushing.
Diet Avoid ingestion of alcohol, hot beverages and spicy foods around the time of taking niacin extended-release tablets to minimize flushing.
Supplements Notify their physician if they are taking vitamins or other nutritional supplements containing niacin or nicotinamide.
Dizziness Notify their physician if symptoms of dizziness occur.
Diabetics If diabetic, to notify their physician of changes in blood glucose.
Pregnancy Discuss future pregnancy plans with your patients, and discuss when to stop niacin extended-release tablets if they are trying to conceive.
Patients should be advised that if they become pregnant, they should stop taking niacin extended-release tablets and call their healthcare professional.
Breastfeeding Women who are breastfeeding should be advised to not use niacin extended-release tablets.
Patients, who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.
TEVA PHARMACEUTICALS USA, INC.
North Wales, PA 19454 Rev.
DOSAGE AND ADMINISTRATION
2 Niacin Extended-Release Tablets 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 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.
Recommended Dosing Week(s) Daily Dose Niacin Extended-Release Tablets Dosage INITIAL TITRATION 1 to 4 500 mg 1 Niacin Extended-Release 500 mg Tablet at bedtime SCHEDULE 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 * After Week 8, titrate to patient response and tolerance.
If response to 1000 mg daily is inadequate, increase dose to 1500 mg daily; may subsequently increase dose to 2000 mg daily.
Daily dose should not be increased more than 500 mg in a 4-week period, and doses above 2000 mg daily are not recommended.
Women may respond at lower doses than men.
Maintenance Dose The daily dosage of Niacin Extended-Release Tablets 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 Tablet 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.
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 Tablet 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 Tablet ingestion.
Equivalent doses of Niacin Extended-Release Tablets 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 Tablet titration schedule (see Table 1 ), and the dose should subsequently be individualized based on patient response.
If Niacin Extended-Release Tablet therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase (see Table 1 ).
Niacin Extended-Release Tablets should be taken whole and should not be broken, crushed or chewed before swallowing.
Dosage in Patients with Renal or Hepatic Impairment Use of Niacin Extended-Release Tablets in patients with renal or hepatic impairment has not been studied.
Niacin Extended-Release Tablets are contraindicated in patients with significant or unexplained hepatic dysfunction.
Niacin Extended-Release Tablets should be used with caution in patients with renal impairment [see Warnings and Precautions ( 5 )].
• Niacin Extended-Release Tablets should be taken at bedtime with a low-fat snack.
( 2 ) • Dose range: 500 mg to 2000 mg once daily.
( 2 ) • Therapy with Niacin Extended-Release Tablets 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 and should not be increased by more than 500 mg in any four week period.
( 2 ) • Maintenance dose: 1000 to 2000 mg once daily.
( 2 ) • Doses greater than 2000 mg daily are not recommended.
( 2 )