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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.
Due to extensive and saturable first-pass metabolism, niacin concentrations in the general circulation are dose dependent and highly variable. Time to reach the maximum niacin plasma concentrations was about 5 hours following NIASPAN. To reduce the risk of gastrointestinal (GI) upset, administration of NIASPAN with a low-fat meal or snack is recommended.
Single-dose bioavailability studies have demonstrated that the 500 mg and 1000 mg tablet strengths are dosage form equivalent but the 500 mg and 750 mg tablet strengths are not dosage form equivalent.
The pharmacokinetic profile of niacin is complicated due to extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. In humans, one pathway is through a simple conjugation step with glycine to form nicotinuric acid (NUA). NUA is then excreted in the urine, although there may be a small amount of reversible metabolism back to niacin. The other pathway results in the formation of nicotinamide adenine dinucleotide (NAD). It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolized to at least N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is further metabolized to two other compounds, N-methyl- 2-pyridone-5-carboxamide (2PY) and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans. At the doses used to treat hyperlipidemia, these metabolic pathways are saturable, which explains the nonlinear relationship between niacin dose and plasma concentrations following multiple-dose NIASPAN administration.
Nicotinamide does not have hypolipidemic activity; the activity of the other metabolites is unknown.
Following single and multiple doses, approximately 60 to 76% of the niacin dose administered as NIASPAN was recovered in urine as niacin and metabolites; up to 12% was recovered as unchanged niacin after multiple dosing. The ratio of metabolites recovered in the urine was dependent on the dose administered.
No pharmacokinetic studies have been performed in this population ( ≤ 16 years) [see Use in Specific Populations].
No pharmacokinetic studies have been performed in this population ( > 65 years) [see Use in Specific Populations].
No pharmacokinetic studies have been performed in this population. NIASPAN should be used with caution in patients with renal disease [see WARNINGS AND PRECAUTIONS].
No pharmacokinetic studies have been performed in this population. 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].
Steady-state plasma concentrations of niacin and metabolites after administration of NIASPAN are generally higher in women than in men, with the magnitude of the difference varying with dose and metabolite. This gender differences observed in plasma levels of niacin and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution. Recovery of niacin and metabolites in urine, however, is generally similar for men and women, indicating that absorption is similar for both genders [see Gender].
Niacin did not affect fluvastatin pharmacokinetics [see DRUG INTERACTIONS].
When NIASPAN 2000 mg and lovastatin 40 mg were co-administered, NIASPAN increased lovastatin Cmax and AUC by 2% and 14%, respectively, and decreased lovastatin acid Cmax and AUC by 22% and 2%, respectively. Lovastatin reduced NIASPAN bioavailability by 2-3% [see DRUG INTERACTIONS].
When NIASPAN 2000 mg and simvastatin 40 mg were co-administered, NIASPAN increased simvastatin Cmax and AUC by 1% and 9%, respectively, and simvastatin acid Cmax and AUC by 2% and 18%, respectively. Simvastatin reduced NIASPAN bioavailability by 2% [see DRUG INTERACTIONS].
Bile Acid Sequestrants
An in vitro study was carried out investigating the niacin-binding capacity of colestipol and cholestyramine. About 98% of available niacin was bound to colestipol, with 10 to 30% binding to cholestyramine [see DRUG INTERACTIONS].
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 (52.0% 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.
NIASPAN 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, NIASPAN 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 NIASPAN dose level (see Gender Effect, below).
Table 3: Lipid Response to
|Treatment||Mean Percent Change from Baseline to Week 16*|
|NIASPAN 1000 mg at bedtime||41||-3||-5||+18||-21||-6|
|NIASPAN 2000 mg at bedtime||41||-10||-14||+22||-28||-16|
|NIASPAN 1500 mg at bedtime||76||-8||-12||+20||-13||-12|
|n = number of patients at
* Mean percent change from baseline for all NIASPAN doses was significantly different (p < 0.05) from placebo.
In a double-blind, multi-center, forced dose-escalation study, monthly 500 mg increases in NIASPAN 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 NIASPAN than men (see Gender Effect, below).
Table 4: Lipid Response in
|Treatment||Mean Percent Change from Baseline*|
|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
‡ Placebo data shown are after 24 weeks of placebo treatment.
* For all NIASPAN doses except 500 mg, mean percent change from baseline was significantly different (p < 0.05) from placebo for all lipid parameters shown.
Pooled results for major lipids from these three placebo-controlled studies are shown below (Table 5).
Table 5: Selected Lipid
Response to NIASPAN in Placebo-Controlled Clinical Studies*
|NIASPAN Dose||Mean Baseline and Median Percent Change from Baseline (25th, 75th Percentiles)|
|1000 mg at bedtime||104|
|Percent Change||-7 (-15, 0)||+14 (+7, +23)||-16 (-34, +3)|
|1500 mg at bedtime||120|
|Percent Change||-13 (-21, -4)||+19 (+9, +31)||-25 (-45, -2)|
|2000 mg at bedtime||85|
|Percent Change||-16 (-26, -7)||+22 (+15, +34)||-38 (-52, -14)|
|* Represents pooled analyses of results; minimum duration on therapy at each dose was 4 weeks.|
Combined data from the three placebo-controlled NIASPAN studies in patients with primary hyperlipidemia and mixed dyslipidemia suggest that, at each NIASPAN dose level studied, changes in lipid concentrations are greater for women than for men (Table 6).
Table 6: Effect of Gender on
NIASPAN Dose Response
|NIASPAN||n||Mean Percent Change from Baseline|
|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
* Percent change significantly different between genders (p < 0.05).
Other Patient Populations
In a double-blind, multi-center, 19-week study the lipid-altering effects of NIASPAN (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).
Table 7: Lipid Response to
NIASPAN in Patients with Low HDL-C
|Mean Baseline and Mean Percent Change from Baseline*|
|Week 19 (% Change)||71||-3||0||+26||-30||-9|
|n = number of patients
* Mean percent change from baseline was significantly different (p < 0.05) for all lipid parameters shown except LDL-C.
† n = 72 at baseline and 69 at week 19.
At NIASPAN 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.
Last reviewed on RxList: 6/8/2015
This monograph has been modified to include the generic and brand name in many instances.
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