Niaspan - Product Information
|Condition:||High Cholesterol, Hyperlipoproteinemia Type V, Elevated Chylomicrons VLDL, Hyperlipoproteinemia Type IV, Elevated VLDL, Hyperlipoproteinemia|
|Class:||Miscellaneous antihyperlipidemic agents, Vitamins|
|Ingredients:||Niacin, Hypromellose, Povidone, Stearic Acid, Polyethylene Glycol|
Indications and Usage
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.
- NIASPAN is indicated to reduce elevated TC, LDL-C, Apo B and TG levels, and to increase HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia.
- 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.
- NIASPAN 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
Addition of NIASPAN did not reduce cardiovascular morbidity or mortality among patients treated with simvastatin in a large, randomized controlled trial (AIM-HIGH) [see Warnings and Precautions].
Dosage and Administration
NIASPAN should be taken at bedtime, after a low-fat snack, and doses should be individualized according to patient response. Therapy with NIASPAN 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||NIASPAN Dosage|
|INITIAL TITRATION||1 to 4||500 mg||1 NIASPAN 500 mg tablet at bedtime|
|SCHEDULE||5 to 8||1000 mg||1 NIASPAN 1000 mg tablet or
2 NIASPAN 500 mg tablets at bedtime
|*||1500 mg||2 NIASPAN 750 mg tablets or
3 NIASPAN 500 mg tablets at bedtime
|*||2000 mg||2 NIASPAN 1000 mg tablets or
4 NIASPAN 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.
The daily dosage of NIASPAN 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 NIASPAN doses than men [see Clinical Studies].
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] may be reduced in frequency or severity by pretreatment with aspirin (up to the recommended dose of 325 mg taken 30 minutes prior to NIASPAN 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 NIASPAN ingestion.
Equivalent doses of NIASPAN should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin [see Warnings and Precautions]. Patients previously receiving other niacin products should be started with the recommended NIASPAN titration schedule (see Table 1), and the dose should subsequently be individualized based on patient response.
If NIASPAN therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase (see Table 1).
NIASPAN 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 NIASPAN in patients with renal or hepatic impairment has not been studied. NIASPAN is contraindicated in patients with significant or unexplained hepatic dysfunction. NIASPAN should be used with caution in patients with renal impairment [see Warnings and Precautions].
Dosage Forms and Strengths
- 500 mg unscored, medium-orange, film-coated, capsule-shaped tablets
- 750 mg unscored, medium-orange, film-coated, capsule-shaped tablets
- 1000 mg unscored, medium-orange, film-coated, capsule-shaped tablets
NIASPAN is contraindicated in the following conditions:
- Active liver disease or unexplained persistent elevations in hepatic transaminases [see Warnings and Precautions]
- Patients with active peptic ulcer disease
- Patients with arterial bleeding
- Hypersensitivity to niacin or any component of this medication [see Adverse Reactions]
Warnings and Precautions
NIASPAN preparations should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to NIASPAN, therapy with NIASPAN should be initiated with low doses (i.e., 500 mg at bedtime) and the NIASPAN dose should then be titrated to the desired therapeutic response [see Dosage and Administration].
Caution should also be used when NIASPAN is 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. NIASPAN is contraindicated in patients with significant or unexplained hepatic impairment [see Contraindications and Warnings and Precautions] 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 NIASPAN therapy.
Mortality and Coronary Heart Disease Morbidity
NIASPAN has 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 163-177 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 40-80 mg/dL, and were randomized to receive NIASPAN 1500-2000 mg/day (n=1718) or matching placebo (IR Niacin, 100-150 mg, n=1696). On-treatment lipid changes at two years for LDL-C were -12.0% for the simvastatin plus NIASPAN group and -5.5% for the simvastatin plus placebo group. HDL-C increased by 25.0% to 42 mg/dL in the simvastatin plus NIASPAN 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 NIASPAN 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 NIASPAN group (16.4%) and in 274 patients in the simvastatin plus placebo group (16.2%) (HR 1.02 [95% CI, 0.87-1.21], 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 NIASPAN group and 15 (0.9%) in the simvastatin plus placebo group, a non-statistically significant result (HR 1.79, [95%CI = 0.95-3.36], p=0.071). The on-treatment ischemic stroke events were 19 for the simvastatin plus NIASPAN group and 15 for the simvastatin plus placebo group [see Adverse Reactions].
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.
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.
NIASPAN 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 NIASPAN.
Niacin preparations have been associated with abnormal liver tests. In three placebo-controlled clinical trials involving titration to final daily NIASPAN doses ranging from 500 to 3000 mg, 245 patients received NIASPAN 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 NIASPAN. In these studies, fewer than 1% (2/245) of NIASPAN patients discontinued due to transaminase elevations greater than 2 times the ULN.
Liver-related tests should be performed on all patients during therapy with NIASPAN. 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.
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 NIASPAN, 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
NIASPAN has been associated with small but statistically significant dose-related reductions in platelet count (mean of -11% with 2000 mg). Caution should be observed when NIASPAN is administered concomitantly with anticoagulants; platelet counts should be monitored closely in such patients.
Increase in Prothrombin Time (PT)
NIASPAN has 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 NIASPAN is 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, NIASPAN has 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.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Clinical Studies Experience
In the placebo-controlled clinical trials database of 402 patients (age range 21-75 years, 33% women, 89% Caucasians, 7% Blacks, 3% Hispanics, 1% Asians) with a median treatment duration of 16 weeks, 16% of patients on NIASPAN and 4% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with NIASPAN that led to treatment discontinuation and occurred at a rate greater than placebo 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 reported adverse reactions (incidence >5% and greater than placebo) in the NIASPAN controlled clinical trial database of 402 patients were flushing, diarrhea, nausea, vomiting, increased cough and pruritus.
In the placebo-controlled clinical trials, flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse reactions (reported by as many as 88% of patients) for NIASPAN. Spontaneous reports suggest that flushing may also be accompanied by symptoms of dizziness, tachycardia, palpitations, shortness of breath, sweating, burning sensation/skin burning sensation, chills, and/or edema, which in rare cases may lead to syncope. In pivotal studies, 6% (14/245) of NIASPAN patients discontinued due to flushing. In comparisons of immediate-release (IR) niacin and NIASPAN, although the proportion of patients who flushed was similar, fewer flushing episodes were reported by patients who received NIASPAN. Following 4 weeks of maintenance therapy at daily doses of 1500 mg, the incidence of flushing over the 4-week period averaged 8.6 events per patient for IR niacin versus 1.9 following NIASPAN.
Other adverse reactions occurring in ≥5% of patients treated with NIASPAN and at an incidence greater than placebo are shown in Table 2 below.
|Placebo-Controlled Studies NIASPAN Treatment@|
|Recommended Daily Maintenance Doses†|
|Placebo||500 mg‡||1000 mg||1500 mg||2000 mg|
|(n = 157)||(n = 87)||(n = 110)||(n = 136)||(n = 95)|
|Cough, Increased||6||3||2||< 2||8|
|Skin and Subcutaneous
Note: Percentages are calculated from the total number of patients in each column.
@ Adverse reactions are reported at the initial dose where they occur.
† Pooled results from placebo-controlled studies; for NIASPAN, n = 245 and median treatment duration = 16 weeks. Number of NIASPAN patients (n) are not additive across doses.
‡ The 500 mg/day dose is outside the recommended daily maintenance dosing range [see Dosage and Administration].
& 10 patients discontinued before receiving 500 mg, therefore they were not included.
In general, the incidence of adverse events was higher in women compared to men.
Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH)
In AIM-HIGH involving 3414 patients (mean age of 64 years, 15% women, 92% Caucasians, 34% with diabetes mellitus) with stable, previously diagnosed cardiovascular disease, all patients received simvastatin, 40 to 80 mg per day, plus ezetimibe 10 mg per day if needed, to maintain an LDL-C level of 40-80 mg/dL, and were randomized to receive NIASPAN 1500-2000 mg/day (n=1718) or matching placebo (IR Niacin, 100-150 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 significantly higher in the simvastatin plus NIASPAN group as compared to the simvastatin plus placebo group. There were 5 cases of rhabdomyolysis reported, 4 (0.2%) in the simvastatin plus NIASPAN group and one (<0.1%) in the simvastatin plus placebo group [see Warnings and Precautions].
Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following additional adverse reactions have been identified during post-approval use of NIASPAN:
Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, and vesiculobullous rash; maculopapular rash; dry skin; tachycardia; palpitations; atrial fibrillation; other cardiac arrhythmias; syncope; hypotension; postural hypotension; 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, and migraine.
Clinical Laboratory Abnormalities
Chemistry: Elevations in serum transaminases [see Warnings and Precautions], LDH, fasting glucose, uric acid, total bilirubin, amylase and creatine kinase, and reduction in phosphorus.
Hematology: Slight reductions in platelet counts and prolongation in prothrombin time [see Warnings and Precautions].
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 and Clinical Pharmacology].
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 NIASPAN [see Clinical Pharmacology].
Concomitant aspirin may decrease the metabolic clearance of nicotinic acid. The clinical relevance of this finding is unclear.
Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension.
Vitamins or other nutritional supplements containing large doses of niacin or related compounds such as nicotinamide may potentiate the adverse effects of NIASPAN.
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.
Use in Specific Populations
Pregnancy Category C.
Animal reproduction studies have not been conducted with niacin or with NIASPAN. 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.
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 NIASPAN in nursing mothers.
Safety and effectiveness of niacin therapy in pediatric patients (≤16 years) have not been established.
Of 979 patients in clinical studies of NIASPAN, 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.
No studies have been performed in this population. NIASPAN should be used with caution in patients with renal impairment [see Warnings and Precautions].
No studies have been performed in this population. NIASPAN should be used with caution in patients with a past history of liver disease and/or who consume substantial quantities of alcohol. Active liver disease, unexplained transaminase elevations and significant or unexplained hepatic dysfunction are contraindications to the use of NIASPAN [see Contraindications and Warnings and Precautions].
Data from the clinical trials suggest that women have a greater hypolipidemic response than men at equivalent doses of NIASPAN.
Supportive measures should be undertaken in the event of an overdose.
How Supplied/Storage and Handling
NIASPAN tablets are supplied as unscored, medium-orange, film-coated, capsule-shaped (containing 500 or 750 mg of niacin) or oval shaped (containing 1000 mg of niacin) tablets, in an extended-release formulation. Tablets are printed with the “a” logo and the tablet strength (500, 750 or 1000). Tablets are supplied in bottles of 30 and 90 as shown below.
500 mg tablets: bottles of 30 - NDC# 0074–3074–30
500 mg tablets: bottles of 90 - NDC# 0074–3074–90
750 mg tablets: bottles of 30 - NDC# 0074–3079–30
750 mg tablets: bottles of 90 - NDC# 0074–3079–90
1000 mg tablets: bottles of 30 - NDC# 0074–3080–30
1000 mg tablets: bottles of 90 - NDC# 0074–3080–90
Storage: Store at room temperature 20° to 25°C (68° to 77°F).
Patient Counseling Information
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 NIASPAN.
The patient should be informed of the following:
NIASPAN tablets should be taken at bedtime, after a low-fat snack. Administration on an empty stomach is not recommended.
NIASPAN tablets should not be broken, crushed or chewed, but should be swallowed whole.
If dosing is interrupted for any length of time, their physician should be contacted prior to restarting therapy; re-titration is recommended.
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 (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 NIASPAN 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.
Avoid ingestion of alcohol, hot beverages and spicy foods around the time of taking NIASPAN to minimize flushing.
Notify their physician if they are taking vitamins or other nutritional supplements containing niacin or nicotinamide.
Notify their physician if symptoms of dizziness occur.
If diabetic, to notify their physician of changes in blood glucose.
Discuss future pregnancy plans with your patients, and discuss when to stop NIASPAN if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking NIASPAN and call their healthcare professional.
Women who are breastfeeding should be advised to not use NIASPAN. Patients, who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.
AbbVie LTD, Barceloneta, PR 00617
For AbbVie Inc.
North Chicago, IL 60064, USA