Niacin: Package Insert and Label Information

NIACIN- niacin tablet, extended release
AvPAK

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.

  1. Niacin extended-release tablets 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.
  2. In patients with a history of myocardial infarction and hyperlipidemia, niacin is indicated to reduce the risk of recurrent nonfatal myocardial infarction.
  3. 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.
  4. Niacin extended-release tablets in combination with a bile acid binding resin is indicated to reduce elevated TC and LDL-C levels in adult patients with primary hyperlipidemia.
  5. 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 niacin extended-release tablets 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)] .

2 DOSAGE AND ADMINISTRATION

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.

Table 1. Recommended Dosing

Week(s)

Daily dose

Niacin Extended-Release Tablets Dosage

INITIAL

TITRATION

1 to 4

500 mg

1 Niacin Extended-Release Tablet 500 mg at bedtime

SCHEDULE

5 to 8

1000 mg

1 Niacin Extended-Release Tablet 1000 mg or

2 Niacin Extended-Release Tablets 500 mg at bedtime

*

1500 mg

3 Niacin Extended-Release Tablets 500 mg at bedtime

*

2000 mg

2 Niacin Extended-Release Tablets 1000 mg or

4 Niacin Extended-Release Tablets 500 mg 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 tablets 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.

Tolerance to 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 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 tablets titration schedule (see Table 1), and the dose should subsequently be individualized based on patient response.

If niacin extended-release tablets 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)] .

3 DOSAGE FORMS AND STRENGTHS

  • 500 mg light orange to orange colored, round shaped, film-coated tablets debossed with ‘AN 321’ on one side and plain on the other side.
  • 1000 mg light orange to orange colored, capsule shaped, film-coated tablets debossed with ‘AN 323’ on one side and plain on the other side

4 CONTRAINDICATIONS

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)]

5 WARNINGS AND PRECAUTIONS

Niacin extended-release preparations should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to niacin extended-release, therapy with niacin extended-release should be initiated with low doses (i.e., 500 mg at bedtime) and the niacin extended-release dose should then be titrated to the desired therapeutic response [see Dosage and Administration (2)] .

Caution should also be used when niacin 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. Niacin is 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 therapy.

5.1 Mortality and Coronary Heart Disease Morbidity

Niacin extended-release 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 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 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 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 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 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 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 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 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 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.

Niacin preparations have been associated with abnormal liver tests. In three placebo-controlled clinical trials involving titration to final daily niacin extended-release doses ranging from 500 to 3000 mg, 245 patients received niacin extended-release 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. In these studies, fewer than 1% (2/245) of niacin extended-release 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. 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, 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 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 niacin extended-release is administered concomitantly with anticoagulants; platelet counts should be monitored closely in such patients.

Increase in Prothrombin Time (PT): Niacin extended-release 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 niacin extended-release 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, niacin extended-release 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.

6 ADVERSE REACTIONS

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.

6.1 Clinical Studies Experience

In the placebo-controlled clinical trials database of 402 patients (age range 21 to 75 years, 33% women, 89% Caucasians, 7% Blacks, 3% Hispanics, 1% Asians) with a median treatment duration of 16 weeks, 16% of patients on niacin extended-release and 4% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with niacin extended-release 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 niacin extended-release 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 niacin extended-release. 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 niacin extended-release patients discontinued due to flushing. In comparisons of immediate-release (IR) niacin and niacin extended-release tablets, although the proportion of patients who flushed was similar, fewer flushing episodes were reported by patients who received niacin extended-release. 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 niacin extended-release.

Other adverse reactions occurring in ≥5% of patients treated with niacin extended-release and at an incidence greater than placebo are shown in Table 2 below.

Table 2. Treatment-Emergent Adverse Reactions by Dose Level in ≥ 5% of Patients and at an Incidence Greater than Placebo; Regardless of Causality Assessment in Placebo-Controlled Clinical Trials

Placebo-Controlled Studies Niacin Extended-release 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.

Adverse reactions are reported at the initial dose where they occur.

@ Pooled results from placebo-controlled studies; for niacin extended-release, n = 245 and median treatment duration = 16 weeks. Number of niacin patients (n) are not additive across doses.

The 500 mg/day dose is outside the recommended daily maintenance dosing range [see Dosage and Administration (2)] .

& 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 to 80 mg/dL, and were randomized to receive niacin extended-release 1500 to 2000 mg/day (n=1718) or matching placebo (IR Niacin, 100 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 significantly higher in the simvastatin plus niacin extended-release group as compared to the simvastatin plus placebo group. There were 5 cases of rhabdomyolysis reported, 4 (0.2%) in the simvastatin plus niacin extended-release group and one (<0.1%) in the simvastatin plus placebo group [see Warnings and Precautions (5.1)] .

Page 1 of 4 1 2 3 4

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2021. All Rights Reserved.