Niaspan

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.

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

In general, the incidence of adverse events was higher in women compared to men.

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].

Postmarketing Experience

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.

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].

You should not take this medication if you are allergic to niacin, or if you have severe liver disease, a stomach ulcer, or active bleeding.

Niacin can cause certain side effects, such as flushing (warmth, itching, redness, or tingly feeling under your skin). These effects can be made worse if you drink alcohol or hot beverages shortly after you take niacin. These effects should disappear over time as you keep taking the medication.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid taking colestipol (Colestid) or cholestyramine (Locholest, Prevalite, Questran) at the same time you take niacin. If you take either of these other medications, take them at least 4 to 6 hours before or after you take niacin.

Niacin is only part of a complete program of treatment that may also include diet, exercise, weight control, and other medications. Follow your diet, medication, and exercise routines very closely.

• Cholesterol
• Diabetes Prescription Insulin Medications
• Heart Attack
• Liver Disease
• Stroke (Signs, Symptoms, Warning Signs)

Before taking Niaspan, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Niaspan or to any of its ingredients.
• have diabetes. Tell your doctor if your blood sugar levels change after you take Niaspan.
• have gout
• have ulcers
• have liver disease
• have jaundice
• have kidney disease
• have heart diseases
• have gallbladder disease
• have bleeding problems
• are pregnant or breastfeeding 

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Niacin is used alone or with other medicines to treat high cholesterol and triglyceride (fat-like substances) levels in the blood. This may help prevent the development of pancreatitis (inflammation of the pancreas) and other problems caused by high levels of cholesterol and triglycerides in the blood. Niacin is also used to help lower risk of heart attack in patients with a history of heart attack and hyperlipidemia.

This medicine is available only with your doctor's prescription.

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.

Maintenance Dose

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 (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 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 (5)]. 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 (5)].

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 (2)].

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 (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 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 (6.1)].

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.

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.

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.

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 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.

Pregnancy

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.

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 Niaspan in nursing mothers.

Pediatric Use

Safety and effectiveness of niacin therapy in pediatric patients (≤16 years) have not been established.

Geriatric Use

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.

Renal Impairment

No studies have been performed in this population. Niaspan should be used with caution in patients with renal impairment [see Warnings and Precautions (5)].

Hepatic Impairment

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 (4.0) and Warnings and Precautions (5.3)].

Gender

Data from the clinical trials suggest that women have a greater hypolipidemic response than men at equivalent doses of Niaspan.

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 Niaspan.

The patient should be informed of the following:

Dosing Time

Niaspan tablets should be taken at bedtime, after a low-fat snack. Administration on an empty stomach is not recommended.

Tablet Integrity

Niaspan 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 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.

Diet

Avoid ingestion of alcohol, hot beverages and spicy foods around the time of taking Niaspan 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 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.

Breastfeeding

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 Inc. 2016

Manufactured by:

AbbVie LTD, Barceloneta, PR 00617

For AbbVie Inc.

North Chicago, IL 60064, USA

03-B385 August, 2016

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, dizziness, itching, vomiting, upset stomach, and flushing (warmth, redness, or tingly feeling).

Applies to niacin: compounding powder, oral capsule, oral capsule extended release, oral liquid, oral tablet, oral tablet extended release

Cardiovascular

Very common (10% or more): Flushing (i.e., warmth, redness, itching, and/or tingling) (up to 88%)
Frequency not reported: Tachycardia, palpitations, atrial fibrillation, other cardiac arrhythmias, syncope, hypotension, postural hypotension[Ref]

Dermatologic

Common (1% to 10%): Rash, pruritus
Frequency not reported: Sweating, skin burning sensation, maculopapular rash, dry skin
Postmarketing reports: Skin discoloration[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 14%), nausea (up to 11%)
Common (1% to 10%): Vomiting
Frequency not reported: Peptic ulcers, eructation, flatulence[Ref]

Hematologic

Postmarketing reports: Slight reductions in platelet counts, prothrombin time prolonged[Ref]

Hypersensitivity

Postmarketing reports: Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, vesiculobullous rash)[Ref]

Hepatic

Postmarketing reports: Hepatitis, jaundice[Ref]

Metabolic

Frequency not reported: Decreased glucose tolerance, gout[Ref]

Musculoskeletal

Frequency not reported: Myalgia, myopathy[Ref]

Nervous system

Frequency not reported: Dizziness, syncope
Postmarketing reports: Migraine, asthenia, paresthesia[Ref]

Ocular

Postmarketing reports: Blurred vision, macular edema[Ref]

Psychiatric

Postmarketing reports: Insomnia, nervousness[Ref]

Other

Frequency not reported: Chills, edema[Ref]

Respiratory

Common (1% to 10%): Cough increased
Frequency not reported: Dyspnea[Ref]

Some side effects of Niaspan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.