Niacin

Uses and Indications

This drug is indicated to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia and mixed dyslipidemia. It is also indicated to reduce the risk of recurrent nonfatal myocardial infarction in patients with a history of myocardial infarction and hyperlipidemia.

In combination with a bile acid binding resin, this drug is indicated to slow the progression or promote regression of atherosclerotic disease in patients with a history of coronary artery disease (CAD) and hyperlipidemia. Additionally, it serves as an adjunct to diet to reduce elevated TC and LDL-C in adult patients with primary hyperlipidemia.

This drug is indicated to reduce TG in adult patients with severe hypertriglyceridemia, particularly in those with serum triglyceride levels over 2,000 mg/dL and elevations of very low-density lipoprotein (VLDL) cholesterol as well as fasting chylomicrons (Type V hyperlipidemia). Therapy may also be considered for subjects with triglyceride elevations between 1,000 and 2,000 mg/dL who have a history of pancreatitis or recurrent abdominal pain typical of pancreatitis.

Limitations of Use: 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 hypercholesterolemia.

Dosage and Administration

Niacin extended-release tablets should be administered at bedtime with a low-fat snack to enhance tolerability. The recommended dosage range for adults is 500 mg to 2,000 mg once daily. Therapy must be initiated at 500 mg at bedtime to minimize the incidence and severity of side effects that may occur during the initial treatment phase. Dosage increases should not exceed 500 mg in any four-week period.

The maintenance dose typically ranges from 1,000 mg to 2,000 mg once daily. Doses greater than 2,000 mg daily are not recommended.

For immediate-release formulations of nicotinic acid, the usual adult dosage is 1 to 2 grams taken two or three times a day, with doses individualized based on the patient's response. Treatment should begin with one-half tablet (250 mg) as a single daily dose following the evening meal. The frequency of dosing and total daily dose may be increased every four to seven days until the desired LDL cholesterol and/or triglyceride levels are achieved or until the first-level therapeutic dose of 1.5 to 2 grams per day is reached. If hyperlipidemia is not adequately controlled after two months at this level, the dosage can be increased at two to four-week intervals to a maximum of 3 grams per day (1 gram three times per day). In patients with significant lipid abnormalities, higher doses may be required, but should generally not exceed 6 grams per day.

It is important to note that sustained-release (modified-release, timed-release) nicotinic acid preparations should not be substituted for equivalent doses of immediate-release (crystalline) nicotinic acid.

Contraindications

Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels, is a contraindication for the use of this medication. It is also contraindicated in patients with active peptic ulcer disease and those experiencing arterial bleeding. Additionally, known hypersensitivity to any component of this medication is a contraindication.

Warnings and Precautions

Severe hepatic toxicity, including fulminant hepatic necrosis, has been reported in patients substituting sustained-release niacin for immediate-release niacin at equivalent doses. Caution is advised in patients who consume substantial quantities of alcohol or have a history of liver disease, as active liver diseases or unexplained transaminase elevations are contraindications for the use of niacin.

Myopathy and Rhabdomyolysis

Myopathy has been observed in patients taking niacin extended-release tablets. The risk for myopathy and rhabdomyolysis is heightened among elderly patients, those with diabetes, renal failure, uncontrolled hypothyroidism, and patients receiving statin therapy. Rare cases of rhabdomyolysis have been associated with the concomitant use of lipid-altering doses (≥1 g/day) of niacin and HMG-CoA reductase inhibitors. Physicians should carefully weigh the benefits and risks of combined therapy and monitor patients for signs of muscle pain, tenderness, or weakness, especially during the initial months of therapy and during dosage adjustments.

Liver Enzyme Monitoring

Persistent elevations in hepatic transaminase levels can occur during niacin therapy. Liver function tests should be performed on all patients before treatment begins, every six to twelve weeks for the first year, and periodically thereafter (approximately every six months). Special attention should be given to patients with elevated transaminase levels; if these levels rise to three times the upper limit of normal and remain persistent, discontinuation of the drug is recommended. Liver biopsy may be considered if elevations persist beyond discontinuation.

Glucose Monitoring

Niacin can increase serum glucose levels. Diabetic or potentially diabetic patients should have their glucose levels closely monitored, particularly during the first few months of therapy or following dose adjustments. A dose-related rise in glucose intolerance may occur, and adjustments to diet or hypoglycemic therapy may be necessary.

General Precautions

Before initiating therapy with niacin, efforts should be made to control hyperlipidemia through diet, exercise, and weight management. Patients with a history of jaundice, hepatobiliary disease, or peptic ulcer should be closely monitored during treatment. Caution is also warranted in patients with unstable angina or in the acute phase of myocardial infarction, especially if they are receiving vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents. Elevated uric acid levels have been noted with niacin therapy, necessitating caution in patients predisposed to gout.

Laboratory Tests

In addition to liver function tests, periodic serum creatine phosphokinase (CPK) and potassium determinations should be considered for patients receiving combined therapy with HMG-CoA reductase inhibitors and niacin.

Emergency Instructions

Patients should be advised to seek emergency medical help if they experience severe side effects or symptoms indicative of liver dysfunction or myopathy. If transaminase levels show evidence of progression, particularly if they rise to three times the upper limit of normal and are persistent, the drug should be discontinued, and medical advice should be sought.

Side Effects

Most common adverse reactions reported in patients taking niacin include:

• Flushing

• Diarrhea

• Nausea

• Vomiting

• Increased cough

• Pruritus

Serious adverse reactions associated with niacin therapy include:

• Severe hepatic toxicity, particularly in patients substituting sustained-release niacin for immediate-release niacin at equivalent doses. Cases of fulminant hepatic necrosis have also been reported.

• Myopathy, with an increased risk for rhabdomyolysis, particularly among elderly patients, those with diabetes, renal failure, uncontrolled hypothyroidism, and patients concurrently treated with statins.

• Persistent elevations in hepatic transaminase levels, necessitating regular monitoring of liver enzymes before and during treatment.

• Increased serum glucose levels, which should be closely monitored in diabetic or potentially diabetic patients, especially during the initial months of therapy or following dose adjustments.

Additional adverse reactions or important notes include:

• Caution is advised when administering niacin to patients with unstable angina or during the acute phase of a myocardial infarction.

• Patients with a history of liver disease, active liver disease, or unexplained persistent elevations in hepatic transaminase levels should not use niacin.

• Active peptic ulcer disease and arterial bleeding are also contraindications for niacin therapy.

• Known hypersensitivity to niacin or its components is a contraindication.

• Other reported adverse reactions include cardiovascular issues such as atrial fibrillation, orthostasis, and hypotension; gastrointestinal disturbances like dyspepsia and jaundice; skin reactions including hyperpigmentation and dry skin; metabolic changes such as decreased glucose tolerance and hyperuricemia; ocular effects like toxic amblyopia and cystoid macular edema; and neurological symptoms such as headache.

Patients should be monitored closely for these adverse reactions, and appropriate adjustments to therapy should be made as necessary.

Drug Interactions

Caution is advised when prescribing niacin in conjunction with statins, as this combination may elevate the risk of myopathy and rhabdomyolysis.

Pharmacokinetic Interactions

• Bile Acid Sequestrants: These agents possess a high binding capacity for niacin and should be administered at least 4 to 6 hours prior to the intake of niacin extended-release tablets to minimize interaction.

Pharmacodynamic Interactions

• Ganglionic Blocking Agents and Vasoactive Drugs: Nicotinic acid may enhance the effects of these medications, potentially leading to postural hypotension.

• Aspirin: The concomitant use of aspirin may reduce the metabolic clearance of nicotinic acid; however, the clinical significance of this interaction remains unclear.

• Alcohol and Hot Drinks: The intake of alcohol or hot beverages alongside niacin may exacerbate side effects such as flushing and pruritus, and their consumption should be avoided during niacin administration.

Pediatric Use

Safety and effectiveness of niacin therapy in pediatric patients (≤16 years) have not been established. This includes all formulations of niacin, such as tablets, extended-release tablets, and film-coated tablets. There is insufficient data to support the use of niacin in children and adolescents.

Geriatric Use

In clinical studies of niacin extended-release tablets, 21% of the 979 patients evaluated were aged 65 and over. No overall differences in safety and effectiveness were observed between elderly patients and younger patients. Additionally, other clinical experiences have not identified significant differences in responses between these groups; however, greater sensitivity in some older individuals cannot be ruled out. Therefore, while no specific dosage adjustments are recommended based solely on age, healthcare providers should monitor geriatric patients closely for any unusual responses to treatment.

Pregnancy

Pregnant patients receiving niacin or niacin extended-release tablets for hyperlipidemia should discontinue the medication upon recognition of pregnancy. For those treated for hypertriglyceridemia, the individual risks and benefits of continuing therapy should be assessed. Patients are advised to inform their healthcare provider of any known or suspected pregnancy.

The potential for embryofetal toxicity associated with niacin at the doses used in niacin extended-release tablets is currently unknown. Available data on the use of niacin in pregnant women are insufficient to determine any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with niacin or niacin extended-release formulations.

It is generally not necessary to treat hypercholesterolemia during pregnancy, as atherosclerosis is a chronic process, and discontinuing lipid-lowering medications is unlikely to adversely affect the long-term management of primary hypercholesterolemia for most patients. The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2% to 4% and 15% to 20%, respectively. Niacin is classified as Pregnancy Category C, indicating that risk cannot be ruled out.

Lactation

Niacin is known to be present in human milk, with the concentration increasing in relation to maternal supplementation. However, the specific effects of niacin, particularly from extended-release formulations, on breastfed infants or on milk production remain unclear.

Due to the potential for serious adverse reactions in nursing infants, including hepatotoxicity, healthcare providers should advise lactating mothers to avoid breastfeeding while using niacin extended-release tablets. Decisions regarding the continuation of nursing or the drug should be made based on the importance of the medication to the mother and the potential risks to the infant.

It is also noted that while it is not definitively known whether niacin is excreted in human milk, the possibility exists that lipid-altering doses of nicotinic acid could pose risks to nursing infants. Therefore, careful consideration and consultation with a healthcare provider are recommended for lactating mothers who require niacin therapy.

Renal Impairment

Patients with renal impairment should be treated with caution when using niacin, particularly the extended-release formulations. The risk of myopathy and rhabdomyolysis is notably increased in this population, especially among elderly patients, those with diabetes, and individuals with uncontrolled hypothyroidism.

While specific dosage adjustments and monitoring guidelines for patients with renal impairment are not provided in the available labeling, the absence of such information necessitates careful consideration by healthcare providers. It is advisable for clinicians to closely monitor these patients for any signs of muscle-related adverse effects, given the heightened risk associated with niacin therapy in the context of renal dysfunction.

In summary, while no formal studies have been conducted to establish clear guidelines for niacin use in patients with renal impairment, the potential for increased adverse effects warrants a cautious approach.

Hepatic Impairment

Severe hepatic toxicity, including fulminant hepatic necrosis, has been reported in patients substituting sustained-release niacin for immediate-release niacin at equivalent doses. Therefore, caution is advised when prescribing niacin to patients with a history of liver disease or those who consume substantial quantities of alcohol. Active liver diseases or unexplained elevations in transaminase levels are contraindications for the use of niacin.

Liver function tests, including serum transaminase levels (ALT and AST), should be performed on all patients during therapy with niacin. Baseline liver enzyme levels should be monitored before treatment initiation, followed by assessments every six to twelve weeks during the first year of therapy, and periodically thereafter (approximately every six months). Special attention should be given to patients who develop elevated serum transaminase levels; in such cases, measurements should be repeated promptly and performed more frequently.

If transaminase levels show evidence of progression, particularly if they rise to three times the upper limit of normal and remain persistent, discontinuation of niacin is recommended. Additionally, liver biopsy should be considered if elevations persist beyond the discontinuation of the drug.

Overdosage

In the event of a Niacin overdose, supportive measures should be undertaken. Symptoms of overdose may include flushing, gastrointestinal disturbances, and potential liver toxicity. It is essential to monitor the patient closely for any adverse effects and provide symptomatic treatment as necessary.

Healthcare professionals are advised to ensure that the patient remains stable and to implement appropriate interventions based on the severity of the symptoms observed. Continuous assessment and supportive care are critical in managing the patient's condition effectively.

Nonclinical Toxicology

Niacin administered to mice for a lifetime as a 1% solution in drinking water was not carcinogenic. The dosage received by the mice was approximately 6 to 8 times the human dose of 3,000 mg/day, as determined on a mg/m² basis. Additionally, niacin was negative for mutagenicity in the Ames test.

No studies have been performed to evaluate the impairment of fertility associated with niacin. Furthermore, there are no available data regarding the carcinogenicity, mutagenicity, or fertility impairment of niacin extended-release formulations.

No information is provided regarding teratogenic or non-teratogenic effects.

Storage and Handling

Niacin is supplied in various forms, including tablets, extended-release tablets, and film-coated extended-release tablets. The product should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as per USP Controlled Room Temperature guidelines.

All formulations must be dispensed in a tight container that includes a child-resistant closure, ensuring safety and compliance with storage requirements. For specific formulations, such as the extended-release tablets, they may also be dispensed in blister punch material.

It is essential to adhere to these storage conditions to maintain the integrity and efficacy of the product.