Prescription Drug Information: Niacin (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

Niacin administered to mice for a lifetime as a 1% solution in drinking water was not carcinogenic. The mice in this study received approximately 6 to 8 times a human dose of 3000 mg/day as determined on a mg/m 2 basis. Niacin was negative for mutagenicity in the Ames test. No studies on impairment of fertility have been performed. No studies have been conducted with niacin extended-release regarding carcinogenesis, mutagenesis, or impairment of fertility.

14 CLINICAL STUDIES

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 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 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 dose level (see Gender Effect , below).

Table 3. Lipid Response to Niacin Extended-Release Therapy

Mean Percent Change from Baseline to Week 16*

Treatment

n

TC

LDL-C

HDL-C

TG

Apo B

Niacin Extended-Release 1000 mg at

41

-3

-5

+18

-21

-6

bedtime

Niacin Extended-Release 2000 mg at

41

-10

-14

+22

-28

-16

bedtime

Placebo

40

0

-1

+4

0

+1

Niacin Extended-Release 1500 mg at

76

-8

-12

+20

-13

-12

bedtime

Placebo

73

+2

+1

+2

+12

+1

n = number of patients at baseline;

* Mean percent change from baseline for all niacin extended-release doses was significantly different ( p < 0.05) from placebo.

In a double-blind, multi-center, forced dose-escalation study, monthly 500 mg increases in niacin extended-release 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 than men (see Gender Effect , below).

Table 4. Lipid Response in Dose-Escalation Study

Mean Percent Change from Baseline*

Treatment

n

TC

LDL- C

HDL-C

TG

Apo B

Placebo

44

-2

-1

+5

-6

-2

Niacin Extended-Release

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;

Placebo data shown are after 24 weeks of placebo treatment.

* For all niacin extended-release 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 Niacin Extended-Release in Placebo-Controlled Clinical Studies*

Mean Baseline and Median Percent Change from Baseline

(25th, 75th Percentiles)

Niacin Extended-Release 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)

* Represents pooled analyses of results; minimum duration on therapy at each dose was 4 weeks.

Gender Effect: Combined data from the three placebo-controlled niacin extended-release studies in patients with primary hyperlipidemia and mixed dyslipidemia suggest that, at each niacin extended-release dose level studied, changes in lipid concentrations are greater for women than for men (Table 6).

Table 6. Effect of Gender on Niacin Extended-Release Dose Response

Mean Percent Change from Baseline

Niacin Extended-Release

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.

* 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 niacin extended-release (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 Niacin Extended-Release in Patients with Low HDL-C

Mean Baseline and Mean Percent Change from Baseline*

n

TC

LDL-C

HDL-C

TG

Apo B

Baseline

88

190

120

31

194

106

(mg/dL)

Week 19

71

-3

0

+26

-30

-9

(% Change)

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 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.

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