Niacinside effects

The following adverse reactions are discussed in greater detail in other sections of the labeling: Mortality and Coronary Heart Disease Morbidity Skeletal Muscle (rhabdomyolysis) Liver Dysfunction Laboratory Abnormalities Most common adverse reactions (incidence >5% and greater than placebo) are flushing, diarrhea, nausea, vomiting, increased cough, and pruritus. Flushing of the skin may be reduced in frequency or severity by pretreatment with aspirin (up to the recommended dose of 325 mg taken 30 minutes prior to niacin extended-release tablets dose). To report SUSPECTED ADVERSE REACTIONS, contact Quagen Pharmaceuticals LLC at 1- 888-344-9603 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

Studies Experience 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. 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 niacin extended-release tablets 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 tablets 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 tablets 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 tablets. 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 tablets 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 tablets. 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 tablets. Other adverse reactions occurring in 5% of patients treated with niacin extended-release tablets 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 Tablets Treatment Pooled results from placebo-controlled studies; for niacin extended-release tablets, n=245 and median treatment duration=16 weeks. Number of niacin extended-release tablets patients (n) are not additive across doses. Recommended Daily Maintenance Doses Adverse reactions are reported at the initial dose where they occur. Placebo (n = 157) % 500 mg The 500 mg/day dose is outside the recommended daily maintenance dosing range. (n = 87) % 1,000 mg (n = 110) % 1,500 mg (n = 136) % 2,000 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 10 patients discontinued before receiving 500 mg, therefore they were not included. 19 68 69 63 55 Note: Percentages are calculated from the total number of patients in each column. 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 niacin extended-release tablets 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 niacin extended-release tablets 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 tablets group and one (<0.1%) in the simvastatin plus placebo group.

6.2 Postmarketing

Experience The following additional adverse reactions have been identified during post-approval use of niacin extended-release tablets. 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.

Cardiac disorders: tachycardia, palpitations, atrial fibrillation, other cardiac arrhythmias Eye disorders: blurred vision, macular edema Gastrointestinal disorders: peptic ulcers, eructation, flatulence Hepatobiliary disorders: hepatitis, jaundice Immune system disorders: hypersensitivity reactions (including anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, and vesiculobullous rash) Metabolism and nutrition disorders: decreased glucose tolerance, gout Musculoskeletal and connective tissue disorders: myalgia, myopathy Nervous system disorders: dizziness, insomnia, asthenia, nervousness, paresthesia, migraine Respiratory, thoracic and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: maculopapular rash, dry skin, sweating, burning sensation/skin burning sensation, skin discoloration, acanthosis nigricans Vascular disorders: syncope, hypotension, postural hypotension Clinical Laboratory Abnormalities Chemistry: Elevations in serum transaminases, 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.