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NIACIN AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Niacin (nicotinic acid) is a water soluble vitamin (vitamin B3) with antilipemic action.
    B) Niacinamide (nicotinamide) is the amide metabolite of niacin.
    C) Acipimox is an antihyperlipidemic analog of niacin.
    D) The combination of lovastatin and extended-release niacin is available in the US as a fixed-dose tablet. Refer to "LOVASTATIN AND RELATED DRUGS" management for further information.

Specific Substances

    A) ACIPIMOX
    1) K-9321
    2) 5-Methylpyrazine-2-carboxylic acid 4-oxide
    3) Molecular Formula: C6-H6-N2-O3
    4) CAS 51037-30-0
    NIACIN
    1) 375
    2) Acidum Nicotinicum
    3) Nicotinic acid
    4) Nikotinsaure
    5) Pyridine-3-carboxylic acid
    6) 3-Carboxypyridine
    7) 3-Pyridinecarboxylic acid
    8) Molecular Formula: C6-H5-N-O2
    9) CAS 59-67-6
    NIACINAMIDE
    1) Nicotinamide
    2) Nicotinamidum
    3) Nicotinic acid amide
    4) Nicotylamide
    5) Vitamin B3
    6) Vitamin PP
    7) Pyridine-3-carboxamide
    8) Molecular Formula: C6-H6-N2-O
    9) CAS 98-92-0
    XANTHINOL NICOTINATE
    1) Nicotinato de xantinol
    2) Xantinol, Nicotinato de
    3) SK-331A
    4) Xanthinol Niacinate
    5) Xanthinol Nicotinate
    6) 7-(2-Hydroxy-3-[(2-hydroxyethyl) methylamino]propyl)theophylline nictoinate
    7) Molecular Formula: C13-H21-N5-O4,C6-H5-N-O2
    8) CAS 437-74-1

Available Forms Sources

    A) FORMS
    1) NIACIN
    a) The following products are available by prescription:
    1) Niacor (Upsher-Smith): 500 mg tablet (Prod Info NIACOR(R) oral tablets, 2000a)
    2) Niaspan (Kos Pharmaceuticals): 500 mg, 750 mg and 100 mg extended-release tablets (Prod Info NIASPAN(R) extended-release oral tablets, 2010)
    3) Nicotinic acid (Niacin) (various manufacturers; eg, Rugby): 500 mg sustained-release capsules; 500 mg timed-release capsules
    b) OTC PRODUCTS: There are numerous OTC products that may contain various amounts of niacin (eg, 100 mg, 250 mg, 500 mg) (Prod Info niacin oral tablets, 2005; Prod Info niacin oral tablets, 2005a; Prod Info niacin oral tablets, 2007).
    c) Lovastatin in an immediate-release formulation and niacin in an extended-release formulation are available in the United States as 20 mg/1000 mg, 20 mg/500 mg, 20 mg/750 mg tablets (Prod Info Advicor(R), niacin extended-release/lovastatin tablets, 2001).
    2) NIACINAMIDE
    a) ORAL: Various products which can include the following doses: 100 mg (OTC), 250 mg (OTC), 500 mg (OTC/Rx) (Prod Info niacinamide oral tablets, 2000; Prod Info niacinamide oral tablets, 2006; Prod Info niacinamide oral tablets, 2006a)
    3) ACIPIMOX
    a) (Olbetam; Adria Laboratories) 250 mg capsules.
    B) USES
    1) NIACIN
    a) Niacin is used as an adjunct to diet for the reduction of elevated total and LDL levels in patients with primary hypercholesterolemia when the response to diet and other nonpharmacologic measures alone has been inadequate (Prod Info NIACOR(R) oral tablets, 2000a).
    b) In addition, niacin is used as an adjunct therapy in adult patients with hyperlipidemia (Types IV and V), at risk of pancreatitis who do not respond adequately to dietary efforts (Prod Info NIACOR(R) oral tablets, 2000a).
    c) COMBINATION PRODUCTS: The combination of lovastatin and extended-release niacin is available in the US as a fixed-dose tablet for the treatment of primary hypercholesterolemia and mixed dyslipidemia (Prod Info Advicor(R), niacin extended-release/lovastatin tablets, 2001).
    d) High dose niacin is being promoted to substance abuse populations in the belief that it enhances elimination of THC, resulting in negative urine drug screen results. There is no evidence that it is efficacious for this indication (Paopairochanakorn et al, 2001).
    e) MASK URINE DRUG SCREENS: Recently there have been reports in the literature that niacin has been taken in attempts to mask drug screening results. Several reports of toxicity have occurred after using niacin for this purpose (Mittal et al, 2007; Heard & Mendoza, 2007).
    2) NIACINAMIDE
    a) Niacinamide is used to prevent and treat niacin deficiency and pellagra; since niacinamide does not cause vasodilation, it is preferred over niacin (S Sweetman , 2002).
    3) ACIPIMOX
    a) Acipimox is used to treat type IIa, IIb, or IV hyperlipoproteinemias (S Sweetman , 2002).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Niacin and niacinamide are water-soluble, B complex vitamins. Niacin is used as an adjunct to diet to reduce elevated total and LDL levels in patients with primary hypercholesterolemia when the response to diet and other nonpharmacologic measures alone has been inadequate. It is also used as an adjunct therapy in adults with hyperlipidemia (Types IV and V) that are at risk for pancreatitis who do not respond adequately to dietary efforts. Niacin can also reduce serum levels of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), while at the same time increasing high-density lipoprotein (HDL) levels. COMBINATION PRODUCTS: Lovastatin and extended-release niacin are available in the US as a fixed-dose tablet for the treatment of primary hypercholesterolemia and mixed dyslipidemia. MISUSE: NIACIN: There have been reports in the literature that niacin has been taken in attempts to mask (eg, marijuana) urine drug screening results.
    B) PHARMACOLOGY: As B complex vitamins, niacin and niacinamide have identical physiological effects. However, these vitamins differ in some of their actions. Niacin produces peripheral vasodilation and flushing, an effect that generally does not occur with niacinamide. Niacinamide is formed in vivo from metabolism of niacin. Niacinamide is an essential precursor of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are the physiologically active forms of niacin. Serving as coenzymes for several dehydrogenases, NAD and NADP are functional groups of electron-transfer agents active in cellular respiration, glycolysis, and lipid synthesis.
    C) EPIDEMIOLOGY: Niacin is widely available; exposure has occurred.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: COMMON: Flushing, pruritus, and gastrointestinal distress are frequent symptoms after oral niacin therapy. OTHER EVENTS: Other adverse effects include dizziness, atrial fibrillation, tachycardia, palpitations, shortness of breath, sweating, chills, edema, syncope, dryness of the skin, abdominal pain, diarrhea, nausea and vomiting, anorexia, stimulation of peptic ulcer, amblyopia, jaundice and elevated hepatic enzymes, myalgia, decrease in glucose tolerance, hyperglycemia, and hyperuricemia. Metabolic acidosis has occurred following large daily doses of sustained-release niacin. Niacin-induced hepatotoxicity is rare, but appears to be dose-related, occurring most frequently in patients receiving 3 g/day or greater for several months.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Clinical events are likely to be an extension of adverse events reported with therapeutic use of niacin products. MILD TO MODERATE TOXICITY: Epigastric (burning) discomfort or abdominal pain, nausea, vomiting, sensation of warmth, chills and intermittent rash (diffuse, red, flat, and coalescent), primarily affecting scalp, face, and legs have been reported after overdose of niacin. Lactic acidosis has been reported after subacute overdose with sustained-release niacin. SEVERE TOXICITY: Severe hypotension has been reported following a massive niacin overdose (11,000 mg). INTENTIONAL MISUSE: Significant toxicity has been reported in a small number of patients following the use of niacin to interfere with urine drug screening test results. Symptoms have included tachycardia, nausea, vomiting, and abdominal pain. Laboratory findings have also included hypo- and hyperglycemia and coagulopathy following some exposures. A teenager developed a prolonged QTc interval, metabolic acidosis and hypoglycemia after ingesting 5.5 g of niacin.
    0.2.20) REPRODUCTIVE
    A) Niacin and extended-release formulations are classified as FDA pregnancy category C when used in treating hyperlipidemia. The combination drug niacin/simvastatin is classified as FDA pregnancy category X. Niacin is excreted in human milk.

Laboratory Monitoring

    A) Monitor vital signs, especially blood pressure, in symptomatic patients.
    B) Symptomatic patients should be monitored for changes in liver function tests.
    C) Monitor fluid, electrolyte, and acid-base status in patients with significant vomiting and/or diarrhea.
    D) Begin continuous cardiac monitoring and obtain a baseline ECG in patients with evidence of tachycardia or dysrhythmias and to evaluate for possible alterations in QT interval.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Overdose information is limited. Treatment is symptomatic and supportive. Monitor vital signs. Nausea and vomiting may develop. Monitor fluids and electrolytes as indicated; replace with IV fluids and electrolytes.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor vital signs including blood pressure. Begin continuous cardiac monitoring and obtain a baseline ECG in patients with evidence of tachycardia or dysrhythmias and to evaluate for possible alterations in QT interval. HYPOTENSION: IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine. ANAPHYLACTIC REACTIONS: IV administration may produce anaphylactic reactions. Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    C) DECONTAMINATION
    1) PREHOSPITAL: Toxicity is more commonly reported after chronic exposure. Gastrointestinal decontamination is generally not required after an acute overdose of immediate-release products. Consider activated charcoal after an acute ingestion of more than 5 g of sustained-release niacin and if the patient is able to maintain their airway or if the airway is protected.
    2) HOSPITAL: Toxicity is more commonly reported after chronic exposure. Gastrointestinal decontamination is generally not required after an acute overdose of immediate-release products. Consider activated charcoal after an acute ingestion of more than 5 g of sustained-release niacin and if the patient is able to maintain their airway or if the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a mild to moderate oral exposure. Shortness of breath can develop with niacin therapy. Monitor pulse oximetry and begin oxygen therapy as needed. In the event of an anaphylactic reaction. Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions or cardiac instability (ie, profound hypotension, dysrhythmias).
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) There is no information regarding the effectiveness of hemodialysis or hemoperfusion for the removal of niacin from plasma. Niacin has a reported plasma protein binding of 20%.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic or with minimal symptoms (ie, gastrointestinal effects) after a minor exposure (1 or 2 tablets in a child) to niacin and are otherwise improving may be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic (ie, ongoing nausea, vomiting, abdominal pain, alterations in blood pressure), need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PHARMACOKINETICS
    1) NIACIN, IMMEDIATE-RELEASE: Time to peak concentration: 30 to 60 minutes. Plasma elimination half-life: 20 to 45 minutes after oral administration of nicotinic acid. It is also dependent on the dose administered. Approximately 88% of an oral dose is eliminated by the kidneys as an unchanged drug and nicotinuric acid, its primary metabolite.
    2) NIACIN, EXTENDED-RELEASE: Time to peak concentration: Approximately 5 hours. Due to extensive and saturable first-pass metabolism, niacin concentrations in the general circulation are dose dependent and highly variable. Approximately 60 to 76% of extended-release niacin was recovered in urine as niacin and its metabolites following single and multiple doses. The ratio of metabolites recovered in the urine is dependent on the dose administered. Niacin is less than 20% bound to human serum protein.
    3) NIACINAMIDE: Time to peak concentration: 1 to 4 hours. Niacinamide and its metabolites are excreted in urine. Elimination half-life: 10 hours.
    4) ACIPIMOX: It is a derivative of niacin. However, unlike niacin, acipimox does not undergo significant metabolism and is mostly excreted in the urine unchanged. Possibly due to this lack of metabolism, acipimox has a longer duration of action and greater hypolipidemic activity than niacin. Time to peak concentration: 2 hours; 86 to 90% renal excretion (almost exclusively cleared unchanged via the kidneys over 12 to 24 hours); elimination half-life: 2 hours; biphasic elimination occurs with a rapid first phase, followed by a slower second phase of 12 to 24 hours.
    I) PITFALLS
    1) Failure to obtain adequate history of exposure.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established.
    1) After ingesting 11,000 mg of niacin within a 12-hour period, a 56-year-old man developed severe, persistent hypotension (BP 58/40 mmHg) in the absence of cutaneous flushing. Following supportive therapy, he recovered completely.
    2) A 16-year-old girl developed epigastric discomfort and rash after taking 330 mg of niacin daily (more than 25 times the recommended daily allowance for a teenager). Symptoms resolved upon discontinuation of therapy.
    3) Two teenagers developed hepatotoxicity and acidosis after ingestion of 5 and 6 g of sustained-release niacin over a 48-hour period.
    B) THERAPEUTIC: ADULT: EXTENDED-RELEASE FORMULATION: Initial: 500 mg orally once daily at bedtime for 4 weeks, then 1000 mg at bedtime for 4 weeks; titrate by tolerability and efficacy but no faster than 500 mg every 4 weeks; usual maintenance dose, 1000 to 2000 mg once daily at bedtime; MAX 2000 mg/day. ADULT: IMMEDIATE-RELEASE FORMULATION: Initial: 100 mg 3 times/day, increase to 1000 mg 3 times/day, MAX 4500 mg/day. PEDIATRIC: IMMEDIATE-RELEASE: Initial: 100 to 250 mg/day in 3 divided doses with meals; increase 100 mg/day weekly or 250 mg/day every 2 to 3 weeks as tolerated; MAX 10 mg/kg/day.

Clinical Effects

Summary Of Exposure

    A) USES: Niacin and niacinamide are water-soluble, B complex vitamins. Niacin is used as an adjunct to diet to reduce elevated total and LDL levels in patients with primary hypercholesterolemia when the response to diet and other nonpharmacologic measures alone has been inadequate. It is also used as an adjunct therapy in adults with hyperlipidemia (Types IV and V) that are at risk for pancreatitis who do not respond adequately to dietary efforts. Niacin can also reduce serum levels of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), while at the same time increasing high-density lipoprotein (HDL) levels. COMBINATION PRODUCTS: Lovastatin and extended-release niacin are available in the US as a fixed-dose tablet for the treatment of primary hypercholesterolemia and mixed dyslipidemia. MISUSE: NIACIN: There have been reports in the literature that niacin has been taken in attempts to mask (eg, marijuana) urine drug screening results.
    B) PHARMACOLOGY: As B complex vitamins, niacin and niacinamide have identical physiological effects. However, these vitamins differ in some of their actions. Niacin produces peripheral vasodilation and flushing, an effect that generally does not occur with niacinamide. Niacinamide is formed in vivo from metabolism of niacin. Niacinamide is an essential precursor of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are the physiologically active forms of niacin. Serving as coenzymes for several dehydrogenases, NAD and NADP are functional groups of electron-transfer agents active in cellular respiration, glycolysis, and lipid synthesis.
    C) EPIDEMIOLOGY: Niacin is widely available; exposure has occurred.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: COMMON: Flushing, pruritus, and gastrointestinal distress are frequent symptoms after oral niacin therapy. OTHER EVENTS: Other adverse effects include dizziness, atrial fibrillation, tachycardia, palpitations, shortness of breath, sweating, chills, edema, syncope, dryness of the skin, abdominal pain, diarrhea, nausea and vomiting, anorexia, stimulation of peptic ulcer, amblyopia, jaundice and elevated hepatic enzymes, myalgia, decrease in glucose tolerance, hyperglycemia, and hyperuricemia. Metabolic acidosis has occurred following large daily doses of sustained-release niacin. Niacin-induced hepatotoxicity is rare, but appears to be dose-related, occurring most frequently in patients receiving 3 g/day or greater for several months.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Clinical events are likely to be an extension of adverse events reported with therapeutic use of niacin products. MILD TO MODERATE TOXICITY: Epigastric (burning) discomfort or abdominal pain, nausea, vomiting, sensation of warmth, chills and intermittent rash (diffuse, red, flat, and coalescent), primarily affecting scalp, face, and legs have been reported after overdose of niacin. Lactic acidosis has been reported after subacute overdose with sustained-release niacin. SEVERE TOXICITY: Severe hypotension has been reported following a massive niacin overdose (11,000 mg). INTENTIONAL MISUSE: Significant toxicity has been reported in a small number of patients following the use of niacin to interfere with urine drug screening test results. Symptoms have included tachycardia, nausea, vomiting, and abdominal pain. Laboratory findings have also included hypo- and hyperglycemia and coagulopathy following some exposures. A teenager developed a prolonged QTc interval, metabolic acidosis and hypoglycemia after ingesting 5.5 g of niacin.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) SUMMARY: Blurred vision due to cystoid macular edema is a rare side effect of niacin (Guyton & Bays, 2007).
    2) CYSTOID MACULOPATHY: Chronic administration of niacin doses of 3 g/day or greater for 1.5 to 4 months resulted in blurred vision, striations, spokes, or radiations around lights, in 4 patients and funduscopic findings of cystoid maculopathy in 2 patients (Millay et al, 1988).
    3) Gass (1973) described three cases of reversible maculopathy with niacin doses as low as 1.5 g/day. Symptoms resolved 4 to 8 weeks after discontinuation of the drug (Gass, 1973).
    4) Blurring of vision and macular edema without leakage resulted from long-term usage of high doses of niacin in 3 reported cases. In one case, raising the nicotinic acid dose from 1 to 4 g daily caused blurred vision within 4 weeks. In the other 2 cases, at doses of 2 g/day and 3 g/day, symptoms developed over a year. In all cases, visual acuity returned within 2 months or less after discontinuation of nicotinic acid (Callanan et al, 1998).
    5) Blurring of the vision has been described rarely with niacinamide (Zackheim et al, 1981).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Atrial fibrillation, tachycardia, palpitations, orthostasis, syncope, and hypotension have been reported with niacin therapy (Prod Info NIASPAN(R) oral extended-release tablets, 2015).
    B) PROLONGED QT INTERVAL
    1) WITH POISONING/EXPOSURE
    a) TIMED RELEASED/CASE REPORT: A 14-year-old boy with a history of marijuana use, ingested 11 500-mg (5.5 g) timed-release niacin tablets to avoid urine drug detection and became ill within 36 hours of exposure. An ECG obtained approximately 8 hours after presentation, revealed a QT interval of 378 ms and a QTc of 511 ms; no arrhythmias were present. By day 3, the QTc duration was 412 ms. The patient had a complete recovery (Mittal et al, 2007). The authors suggested that the patient's increased QTc interval was secondary to metabolic acidosis.
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) NIACIN: After ingesting 11,000 mg of niacin within a 12 hour period, a 56-year-old man developed severe hypotension (BP 58/40 mm Hg) in the absence of cutaneous flushing. Despite intravenous infusion of over 4 L of normal saline, he remained hypotensive, requiring intravenous dopamine infusion for 12 hours. Serum niacin levels at 48 and 96 hours postingestion were 8.2 mcg/mL and 5.6 mcg/mL, respectively (Mularski et al, 2006).
    b) ACIPIMOX: Vomiting and hypotension were reported in one patient after oral administration of acipimox 100 mg. Although symptoms were not severe, the patient was not rechallenged (Bonadonna et al, 1985).
    D) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Symptoms reported in 16 patients with niacin exposure included tachycardia, flushing, nausea, vomiting, and abdominal pain (Heard & Mendoza, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Shortness of breath has been reported with therapeutic use of niacin (Prod Info NIASPAN(R) oral extended-release tablets, 2015).
    b) Asthma may be aggravated because of histamine release associated with ingestion of nicotinic acid (Alhadeff et al, 1984).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) NIACIN: Headache has been reported with niacin therapy (Prod Info NIASPAN(R), 2005).
    b) NIACINAMIDE: Headache has occurred with administration of therapeutic or high doses of niacinamide (300 mg to 6 g daily) (Hoffer, 1969; Zackheim et al, 1981; Zackheim, 1978; Vague et al, 1989).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) NIACIN: Dizziness has been reported following therapy with niacin (Prod Info NIASPAN(R) oral extended-release tablets, 2015).
    b) NIACINAMIDE: Dizziness has been observed occasionally during niacinamide therapy (Hulshof & Vermeij, 1987).
    2) WITH POISONING/EXPOSURE
    a) NIACIN: Dizziness has been reported following the intentional use of niacin in two adolescents (Mittal et al, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Stimulation of peptic ulcer, jaundice, nausea, vomiting, abdominal pain, and diarrhea have been reported with niacin therapy (Prod Info NIASPAN(R) oral extended-release tablets, 2015; Joseph et al, 2006; Knopp, 1989; Figge et al, 1988).
    b) Severe dental and gingival pain developed in 2 men after taking niacin for 5 months for dyslipidemia. In both cases, pain began when the niacin doses were increased. Discontinuance of niacin relieved the pain (Leighton et al, 1998).
    c) NIACINAMIDE: Nausea, vomiting, diarrhea, and other gastrointestinal complaints have been reported during niacinamide therapy, particularly with large doses (Zackheim et al, 1981; Zackheim, 1978; Hoffer, 1969; Hawkins, 1968; Vague et al, 1989; Hulshof & Vermeij, 1987).
    d) A gastrointestinal flu-like syndrome with persistent vomiting has been reported in some patients following administration of high doses (3 to 12 g daily) of niacinamide for the ineffective treatment of schizophrenia (Hawkins, 1968).
    e) ACIPIMOX
    1) Vomiting and hypotension were reported in one patient after oral administration of acipimox 100 mg. Although symptoms were not severe, the patient was not rechallenged (Bonadonna et al, 1985).
    2) Acipimox-related abdominal pain, bloating, and heartburn have occasionally led to premature discontinuation of acipimox therapy (Barlow et al, 1990; Branchi et al, 1989).
    3) Loose stools and mild gastric upset have been reported infrequently in patients receiving acipimox; however, these effects have not led to premature discontinuation of therapy (Lintott et al, 1989).
    2) WITH POISONING/EXPOSURE
    a) SUMMARY: Epigastric or abdominal pain, burning sensation, nausea, and vomiting have been reported following niacin exposure (Guyton & Bays, 2007; Mittal et al, 2007; Heard & Mendoza, 2007; Mularski et al, 2006; Menna, 1993).
    b) NIACIN/CASE REPORTS: A 14-year-old boy with a history of marijuana use, ingested 11 500-mg (5.5 g) timed-release niacin tablets to avoid urine drug detection, and became ill within 36 hours of exposure. Upon admission, the patient had 6 hours of nausea, vomiting and upper abdominal pain. Following supportive care, the patient made a complete recovery. A 17-year-old girl with a history of marijuana and ecstasy use also developed nausea and vomiting after ingesting 5 500-mg niacin tablets (formulation unknown) to avoid drug detection (Mittal et al, 2007).
    c) NIACIN/CASE SERIES: Symptoms reported in 16 patients with niacin exposure included nausea, vomiting, and abdominal pain (Heard & Mendoza, 2007).
    d) NIACIN/CASE REPORT: After ingesting 11,000 mg of niacin, a 56-year-old man with a history of schizophrenia developed severe hypotension, burning abdominal and chest pain. Following supportive therapy, he recovered without further sequelae (Mularski et al, 2006).
    e) NIACIN/CASE REPORT: Epigastric discomfort, sensation of warmth, chills and intermittent rash (diffuse, red, flat, and coalescent), primarily affecting scalp, face, and legs developed in a 16-year-old girl after receiving megavitamin therapy containing 330 mg (more than 25 times the recommended daily allowance for a teenager) of niacin daily. Symptoms resolved upon discontinuation of the megavitamin therapy (Menna, 1993).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Niacin-induced hepatotoxicity is rare, but appears to be dose-related, occurring most frequently in patients receiving 3 g/day or greater, usually for a minimum of 3 months, but occasionally occurs within a few days or weeks after switching to a sustained release product (Earthman et al, 1991; Dalton & Berry, 1992). Patients will typically present with jaundice, pruritus, nausea, malaise, hepatomegaly, and mild to moderate elevations in serum bilirubin, alkaline phosphatase, and liver enzymes (Prod Info NIASPAN(R) oral extended-release tablets, 2015; Joseph et al, 2006; Kristensen & Olcott, 1999; Mullin et al, 1989; Figge et al, 1988; Goldstein, 1988; Clementz & Holmes, 1987; Patterson et al, 1983).
    b) Isolated cases of fulminant hepatic failure have been reported in patients who have substituted sustained-release niacin products for immediate-release niacin at equivalent doses (Prod Info NIASPAN(R) oral extended-release tablets, 2015; Kristensen & Olcott, 1999; Mullin et al, 1989; Figge et al, 1988; Clementz & Holmes, 1987).
    c) Sustained-release niacin has been associated with a greater degree of hepatotoxicity than has immediate-release niacin (Crouse, 1996).
    d) Prominent features on liver biopsy include parenchymal necrosis with centrilobular cholestasis and sometimes portal fibrosis and pseudolobule formation (Patterson et al, 1983).
    e) NIACIN/CASE REPORT: Nausea, vomiting, and fever, accompanied by elevated liver enzymes in serum and apparent fatty infiltration of the liver in a 52-year-old quadriplegic man were initially attributed to a possible intrahepatic tumor. It was then discovered that the patient had been taking oral niacin 2000 mg/day for 5 months. When niacin was discontinued, the liver chemistries returned to normal within 4 days and the nausea and vomiting abated. Hepatic lesions had regressed by 1 month and were completely resolved at 9 months. The authors caution that niacin-induced hepatic steatosis with concurrent hepatic dysfunction can mimic neoplasia (Kristensen & Olcott, 1999).
    f) Elevations in liver function tests and liver damage (including obstructive jaundice and parenchymal hepatic cell injury) have been reported with administration of niacinamide in relatively large doses (Zackheim et al, 1981; Hoffer, 1969; Winter & Boyer, 1973).
    g) NIACINAMIDE/CASE REPORT: Parenchymal-cell injury, portal fibrosis, and cholestasis were reported in a 35-year-old schizophrenic man receiving niacinamide 9 g daily. Hepatotoxic effects were reversible and reproducible upon rechallenge (Winter & Boyer, 1973).
    2) WITH POISONING/EXPOSURE
    a) EXTENDED-RELEASE/CASE REPORTS: Hepatotoxicity with elevated transaminases, coagulopathy, and anion gap acidosis were reported in two patients after an intentional ingestion of 5 and 6 gs of sustained-release niacin over a 48-hour period prior to urine drug testing, in the belief it would enhance excretion of illicit drugs. Symptoms and laboratory abnormalities resolved within 72 hours (Paopairochanakorn et al, 2001).
    b) TIMED-RELEASE/CASE REPORT: Elevated liver enzymes (alanine aminotransferase (ALT): 92 International Units/L (normal 10 to 45); aspartate aminotransferase (AST): 81 International Units/L (normal: 15 to 40)) were reported in a 14-year-old boy following the intentional ingestion of 5.5 g of timed-release niacin. The values peaked by day 4, with an AST of 193 International Units/L and an ALT of 344 International Units/L. Metabolic acidosis and leukocytosis (WBC 54,000/microliter) were also present. Following supportive care the patient had a complete recovery (Mittal et al, 2007).
    B) WEIGHT LOSS FINDING
    1) WITH THERAPEUTIC USE
    a) NIACIN/CASE REPORT: Significant weight loss and jaundice were reported in a 79-year-old man who had was taking niacin. The patient had elevated alkaline phosphatase [2,315 International Units/L (normal: 37 to 147 International Units /L)], gamma glutamyltranspeptidase [2,807 International Units/L (normal: 1 to 50 International Units/L)], and bilirubin levels [T. bilirubin: 6.9 mg/dL (normal: 0.3 to 1.5 mg/dL)]. Niacin was discontinued and the patient gradually gained back weight. Within 2 months the lab values had returned to normal (Joseph et al, 2006).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Lactic acidosis and hypoglycemia were reported in a 41-year-old man who had been taking niacin 1500 mg/day for a year without incident, then increased his dose to 3000 mg/day of a sustained release product. One month after the dose increase, he developed nausea and vomiting with mild transaminitis. He discontinued medications, but symptoms recurred one week after resuming niacin. Again he recovered, but resumed niacin. On the third presentation, he had an anion gap of 32 mEq/L with a lactate level of 13 mEq/L. Acidosis and hypoglycemia resolved within 24 hours after dextrose therapy (Earthman et al, 1991).
    B) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 14-year-old boy with a history of marijuana use, ingested 11 500-mg (5.5 g) timed-release niacin tablets to avoid urine drug detection and became ill within 36 hours of exposure. An initial ABG showed evidence of metabolic acidosis (pH 6.90, PaCO2 26 mmHg, PaO2 119 mm Hg, and bicarbonate 6.3 mmol/L) along with elevated liver enzymes. Less severe metabolic acidosis (pH 7.32, pCO2 32 mmHg, PO2 124 mmHg and bicarbonate 16 mmol/L) was also observed in a 17-year-old girl after ingesting 5 500-mg niacin tablets (formulation unknown). Both patients improved following supportive care (Mittal et al, 2007).
    C) INCREASED ANION GAP
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Anion gap acidosis developed in a 67-year-old woman 2 days after switching to a sustained-release niacin product. She presented with fatigue, diaphoresis, hypothermia, anion gap of 24 mEq/L, mild elevation of transaminases, and coagulopathy. Toxicity resolved within 3 days(Dalton & Berry, 1992).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Increased anion gap acidosis was described in two patients who acutely ingested 5 and 6 g of sustained-release niacin in preparation for a urine drug test. Anion gap was 18 in one patient and 24 in the other. Both had concomitant hepatotoxicity (Paopairochanakorn et al, 2001).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLOOD COAGULATION DISORDER
    1) WITH POISONING/EXPOSURE
    a) NIACIN/CASE REPORT: A 17-year-old girl, with a history of marijuana and ecstasy use, intentionally ingested 5 500-mg niacin tablets (formulation unknown) to avoid drug detection. At presentation, prothrombin time was 20.9 seconds (normal: 10.3 to 12.8 seconds) with an INR of 3.1. Prothrombin time peaked at 26.9 seconds, but the level decreased to 23.4 seconds within 24 hours. The INR also decreased to 2.29 (Mittal et al, 2007).
    B) LEUKOCYTOSIS
    1) WITH POISONING/EXPOSURE
    a) TIMED-RELEASE/CASE REPORT: Approximately 36 hours after exposure, leukocytosis (WBC 54,000/microliter (76% segmented neutrophils and 8% bands) was noted in a 14-year-old boy following intentional ingestion of 5.5 g of timed-release niacin. Metabolic acidosis, hypoglycemia and elevated liver enzymes were also present. By day 3, the WBC was 18,300/microliter. The patient recovered completely following supportive care (Mittal et al, 2007).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) Severe generalized flushing and a sensation of warmth, particularly in the area of the face, neck and ears is a common side effect and usually subsides after several weeks (Prod Info NIASPAN(R) oral extended-release tablets, 2015). Skin flush disappears when plasma niacin levels are steady or falling (Wilson & Douglass, 1986).
    b) Onset of flushing occurred at 4.1 to 4.8 hours post-dose with extended-release niacin (Niaspan(R)) 2000 mg/day and at 2.6 to 3.6 hours post-dose with Niaspan(R) 1000 mg/day (Morgan et al, 1998).
    c) A progressive decrease in flushing occurs with prolonged treatment (Goldberg, 1998).
    d) Pruritus may be treated with antihistamines if it is persistent. Keratosis nigrican (acanthosis nigricans) requires drug discontinuation (Anon, 1997) and normally reverses after withdrawal of niacin (Figge et al, 1988).
    e) An acute onset of rash, pruritus, and a sensation of warmth was reported in 69 persons after ingestion of niacin 190 mg contained in pumpernickel bagels (CDC, 1983).
    2) WITH POISONING/EXPOSURE
    a) NIACIN/CASE REPORT: A 16-year-old girl developed epigastric discomfort, sensation of warmth, chills and intermittent rash (diffuse, red, flat, and coalescent), primarily affecting her scalp, face, and legs. She admitted to seeing a nutritionist who had put her on megavitamin therapy containing 330 mg (more than 25 times the recommended daily allowance for a teenager) of niacin daily. Symptoms resolved upon discontinuation of the megavitamin therapy (Menna, 1993).
    b) NIACIN/CASE REPORTS: Two adults each reported flushing, with one developing a burning sensation while the other had an itchy erythematous rash, after ingesting niacin prior to a pre-employment urine drug screen. Symptoms resolved spontaneously in both patients (Mittal et al, 2007).
    c) NIACIN/CASE SERIES: Symptoms reported in 16 patients with niacin exposure included flushing, tachycardia, nausea, vomiting, and abdominal pain (Heard & Mendoza, 2007).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) DRUG-INDUCED MYOPATHY
    1) WITH THERAPEUTIC USE
    a) Myalgia (fever, muscle aching or cramping, fatigue) has been reported following therapy with niacin (Prod Info NIASPAN(R) oral extended-release tablets, 2015).
    b) Litin & Anderson (1989) reported 3 additional patients that developed myopathy (severe leg cramps) associated with nicotinic acid therapy for hypercholesterolemia. In each case, the myopathy improved after discontinuation of nicotinic acid (Litin & Anderson, 1989).
    c) NIACIN/CASE REPORT: A chronic alcoholic developed myopathy several months after he underwent treatment with nicotinic acid (niacin) for cholesterol reduction. The myopathy resolved after discontinuation of nicotinic acid (Goldstein, 1989).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ABNORMAL GLUCOSE LEVEL
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia has been reported with niacin use (Guyton & Bays, 2007).
    b) EXTENDED-RELEASE: Extended release niacin at a dose of 2000 mg/day was associated with a 5% increase in fasting plasma glucose. Hyperglycemia is related to insulin resistance (Guyton & Bays, 2007).
    c) In patients with noninsulin-dependent diabetes mellitus with dyslipidemia, niacin treatment induced a deterioration of glycemic control and a consistent increase in plasma uric acid levels (Crouse, 1996; Garg & Grundy, 1990; Figge et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) NIACIN/CASE REPORT: A 14-year-old boy with a history of marijuana use, ingested 11 500-mg (5.5 g) timed-release niacin tablets to avoid urine drug detection and became ill within 36 hours of exposure. Initial blood sugar was 26 mg/dL, with 25 mL of 50% dextrose given. Approximately 8 hours after presentation, blood glucose was 207 mg/dL. Urinalysis was negative for glucose, but 2+ ketones were present. Treatment included an insulin infusion for 20 hours for a tentative diagnosis of diabetic ketoacidosis, which was later ruled out. Blood sugar stabilized and remained normal until discharge (Mittal et al, 2007).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) NIACIN: Anaphylactic reactions (skin rash, itching, wheezing) have been reported after intravenous administration of niacin (Prod Info NIASPAN(R) oral extended-release tablets, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Niacin and extended-release formulations are classified as FDA pregnancy category C when used in treating hyperlipidemia. The combination drug niacin/simvastatin is classified as FDA pregnancy category X. Niacin is excreted in human milk.
    3.20.3) EFFECTS IN PREGNANCY
    A) NIACIN
    1) It is not known if niacin (at doses used for lipid disorders) causes fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. If a woman receiving niacin for primary hyperlipidemia (Types lla or llb) becomes pregnant, the drug should be discontinued. If a woman being treated with niacin for hypertriglyceridemia (Types lV and V) conceives, the benefits and risks of continued therapy should be assessed on an individual basis. All statins are contraindicated in pregnant and nursing women. CAUTION: If a woman of childbearing potential, is administered niacin with a statin refer to the pregnancy category and product labeling for the statin (Prod Info NIASPAN(R) extended-release oral tablets, 2010; Prod Info SIMCOR(R) extended-release oral tablets, 2008).
    B) PREGNANCY CATEGORY
    1) NIACIN
    a) Niacin and extended-release formulations are classified as FDA pregnancy category C (Prod Info NIASPAN(R) extended-release oral tablets, 2010; Prod Info Niaspan(R) niacin extended-release tablets, 2003).
    C) ANIMAL STUDIES
    1) COMBINATION PRODUCTS LOVASTATIN/NIACIN: Animal reproductive studies with the combination product of lovastatin and niacin have not been conducted in humans. It is not known whether usual doses of niacin used for lipid disorders can cause fetal harm or affect reproductive capacity. Congenital anomalies have been reported rarely following intrauterine exposure of HMG-CoA reductase inhibitors. In a prospective review of approximately 100 pregnant women exposed to lovastatin or related HMG-CoA reductase inhibitors, the frequency of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed that which would be expected in the general population. The frequency of congenital anomalies is adequate only to exclude a 3- to 4-fold increase over the background incidence. Of the 100 prospectively followed pregnancies, 89% initiated lovastatin/niacin prior to pregnancy and discontinued treatment during the first trimester after pregnancy was identified (Prod Info ADVICOR(R) oral tablets, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Niacin is known to be excreted in human milk; however the actual infant dose as a percent of the maternal dose is not known. Due to the otential for serious adverse reactions in nursing infants from lipid-altering doses of nicotinic acid, a decision should be made as to whether to discontinue nursing or to discontinue the drug. No studies have been conducted in nursing mothers (Prod Info NIASPAN(R) extended-release oral tablets, 2010; Prod Info SIMCOR(R) extended-release oral tablets, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, especially blood pressure, in symptomatic patients.
    B) Symptomatic patients should be monitored for changes in liver function tests.
    C) Monitor fluid, electrolyte, and acid-base status in patients with significant vomiting and/or diarrhea.
    D) Begin continuous cardiac monitoring and obtain a baseline ECG in patients with evidence of tachycardia or dysrhythmias and to evaluate for possible alterations in QT interval.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic or with minimal symptoms (ie, gastrointestinal effects) after a minor exposure (1 or 2 tablets in a child) to niacin and are otherwise improving may be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic (ie, ongoing nausea, vomiting, abdominal pain, alterations in blood pressure), need to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs, especially blood pressure, in symptomatic patients.
    B) Symptomatic patients should be monitored for changes in liver function tests.
    C) Monitor fluid, electrolyte, and acid-base status in patients with significant vomiting and/or diarrhea.
    D) Begin continuous cardiac monitoring and obtain a baseline ECG in patients with evidence of tachycardia or dysrhythmias and to evaluate for possible alterations in QT interval.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Toxicity is more commonly reported after chronic exposure. Gastrointestinal decontamination is generally not required after acute overdose of immediate release products. Consider decontamination of acute ingestion of more than 5 g of sustained release niacin.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Toxicity is more commonly reported after chronic exposure. Gastrointestinal decontamination is generally not required after acute overdose of immediate release products. Consider decontamination of acute ingestion of more than 5 g of sustained release niacin.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Overdose information is limited. Treatment is symptomatic and supportive. Monitor vital signs. Nausea and vomiting may develop. Monitor fluids and electrolytes as indicated; replace with IV fluids and electrolytes.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Monitor vital signs including blood pressure. Begin continuous cardiac monitoring and obtain a baseline ECG in patients with evidence of tachycardia or dysrhythmias and to evaluate for alterations in QT interval. HYPOTENSION: IV 0.9% NaCl at 10 mL to 20 mL/kg, dopamine, norepinephrine. ANAPHYLACTIC REACTIONS: IV administration may produce anaphylactic reactions. Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    B) MONITORING OF PATIENT
    1) Monitor vital signs, especially blood pressure, in symptomatic patients.
    2) Symptomatic patients should be monitored for changes in liver function tests.
    3) Monitor fluid, electrolyte, and acid-base status in patients with significant vomiting and/or diarrhea.
    4) Begin continuous cardiac monitoring and obtain a baseline ECG in patients with evidence of tachycardia or dysrhythmias and to evaluate for possible alterations in QT interval.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) LACK OF INFORMATION
    1) There is insufficient data on the potential of the dialyzability of niacin (Prod Info Advicor(R) oral extended-release tablets, 2012). There is also no information regarding the effectiveness of hemoperfusion for the removal of niacin from plasma.
    2) Acipimox is efficiently removed with hemodialysis. In uremic patients, elimination of acipimox was negligible until initiation of hemodialysis; the intradialytic half-life was approximately 2.6 hours (Bonadonna et al, 1985).

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established.
    1) After ingesting 11,000 mg of niacin within a 12-hour period, a 56-year-old man developed severe, persistent hypotension (BP 58/40 mmHg) in the absence of cutaneous flushing. Following supportive therapy, he recovered completely.
    2) A 16-year-old girl developed epigastric discomfort and rash after taking 330 mg of niacin daily (more than 25 times the recommended daily allowance for a teenager). Symptoms resolved upon discontinuation of therapy.
    3) Two teenagers developed hepatotoxicity and acidosis after ingestion of 5 and 6 g of sustained-release niacin over a 48-hour period.
    B) THERAPEUTIC: ADULT: EXTENDED-RELEASE FORMULATION: Initial: 500 mg orally once daily at bedtime for 4 weeks, then 1000 mg at bedtime for 4 weeks; titrate by tolerability and efficacy but no faster than 500 mg every 4 weeks; usual maintenance dose, 1000 to 2000 mg once daily at bedtime; MAX 2000 mg/day. ADULT: IMMEDIATE-RELEASE FORMULATION: Initial: 100 mg 3 times/day, increase to 1000 mg 3 times/day, MAX 4500 mg/day. PEDIATRIC: IMMEDIATE-RELEASE: Initial: 100 to 250 mg/day in 3 divided doses with meals; increase 100 mg/day weekly or 250 mg/day every 2 to 3 weeks as tolerated; MAX 10 mg/kg/day.

Therapeutic Dose

    7.2.1) ADULT
    A) NIACIN
    1) IMMEDIATE-RELEASE FORMULATION
    a) USUAL ADULT DOSE: 1 to 2 g administered 2 or 3 times daily (Prod Info NIACOR(R) oral tablet, 2005).
    1) HYPERLIPIDEMIA: INITIAL DOSE: 250 mg as a single daily dose following the evening meal; increase the dose every 4 to 7 days until the desired LDL cholesterol and/or triglyceride level is reached. Maximum dose: 6 g/day (Prod Info NIACOR(R) oral tablet, 2005).
    a) Immediate-release niacin is indicated as an adjunct to diet, alone or in combination with a bile acid binding resin to reduce total and LDL cholesterol in patients with primary hypercholesterolemia (types IIa and IIb), when the response to diet restrictions is inadequate; also indicated as adjunctive therapy for very high serum triglyceride levels (Types IV and V hyperlipidemia) in patients who present a risk of pancreatitis and who have not responded adequately to dietary restrictions (Prod Info NIACOR(R) oral tablet, 2005)
    2) EXTENDED-RELEASE FORMULATION
    a) INITIAL THERAPY: 500 mg orally once daily at bedtime for 4 wk, then 1000 mg at bedtime for 4 wk; titrate by tolerability and efficacy, but no faster than 500 mg every 4 weeks; usual maintenance dose, 1000 to 2000 mg once daily at bedtime; MAX 2000 mg/day (Prod Info NIASPAN(R) oral extended-release tablets, 2015).
    1) Extended-release niacin is indicated as an adjunct to diet when the response to diet has been inadequate for the following (Prod Info NIASPAN(R) oral extended-release tablets, 2015):
    1) Reducing elevated total cholesterol, LDL cholesterol, Apo B, and triglyceride levels, and to increase HDL cholesterol in patients with primary hyperlipidemia and mixed dyslipidemia
    2) Reducing the risk of recurrent nonfatal myocardial infarction in patients with a history of myocardial infarction and hyperlipidemia
    3) Slowing the progression or promoting the regression of atherosclerotic disease in combination with a bile acid binding resin in patients with a history of coronary artery disease and hyperlipidemia
    4) Reducing elevated total cholesterol and LDL cholesterol in combination with a bile acid binding resin in patients with primary hyperlipidemia
    5) Treatment of very high serum triglyceride levels (Types IV and V hyperlipidemia) in patients who present a risk of pancreatitis and who have not responded adequately to dietary modifications
    7.2.2) PEDIATRIC
    A) NIACIN EXTENDED-RELEASE FORMULATION
    1) INITIAL THERAPY IN PATIENTS GREATER THAN 16 YEARS: 500 mg orally once daily at bedtime for 4 wk, then 1000 mg at bedtime for 4 wk; titrate by tolerability and efficacy, but no faster than 500 mg every 4 weeks; usual maintenance dose, 1000 to 2000 mg once daily at bedtime; MAX 2000 mg/day (Prod Info NIASPAN(R) oral extended-release tablets, 2015).
    a) Extended-release niacin is indicated as an adjunct to diet when the response to diet has been inadequate for the following (Prod Info NIASPAN(R) oral extended-release tablets, 2015):
    1) Reducing elevated total cholesterol, LDL cholesterol, Apo B, and triglyceride levels, and to increase HDL cholesterol in patients with primary hyperlipidemia and mixed dyslipidemia
    2) Reducing the risk of recurrent nonfatal myocardial infarction in patients with a history of myocardial infarction and hyperlipidemia
    3) Slowing the progression or promoting the regression of atherosclerotic disease in combination with a bile acid binding resin in patients with a history of coronary artery disease and hyperlipidemia
    4) Reducing elevated total cholesterol and LDL cholesterol in combination with a bile acid binding resin in patients with primary hyperlipidemia
    5) Treatment of very high serum triglyceride levels (Types IV and V hyperlipidemia) in patients who present a risk of pancreatitis and who have not responded adequately to dietary modifications
    B) NIACINAMIDE
    1) NIACINAMIDE 400 milligrams orally daily was effective in the treatment of a pellagra-like syndrome possibly related to VALPROIC ACID therapy (500 milligrams daily for 6 weeks) in a 10-year-old epileptic boy. Erythema and abdominal cramps resolved within 48 hours of initiation of therapy. The authors speculate that VALPROIC ACID may interfere with NIACIN utilization in certain instances. However, nutritional deficiency could not be ruled out in this case (Gillman & Sandyk, 1984).
    2) NIACINAMIDE 250 milligrams orally daily was effective in the treatment of HARTNUP DISEASE in a 12-year-old boy presenting with pellagra and cerebellar ataxia. Skin lesions disappeared following 2 months of therapy, with resolution of cerebellar signs being observed after 4 months (Baron et al, 1956).
    3) In a double-blind study involving 35 children and adolescents with newly-diagnosed type I diabetes, NIACINAMIDE in maximum doses of 1.5 grams daily did not preserve insulin secretion (Chase et al, 1990). During the 1-year study, values of glycosylated hemoglobin and mean insulin dosages were similar for the NIACINAMIDE and placebo groups; fasting and glucagon-stimulated C-peptide levels, which were similar at initiation of therapy, did not differ after 4 and 12 months, and no differences in remission rates were observed between the 2 groups.

Maximum Tolerated Exposure

    A) CASE REPORT: A 23-year-old man ingested an estimated 22.5 g of a sustained release formulation of niacin over 2 days to reportedly pass a preemployment urine exam. He was admitted with confusion, hemolytic anemia, thrombocytopenia, coagulopathy, acute renal failure and fever. Nicotinic acid levels were 5.52 and 2.18 mcg/mL on days 3 and 5, respectively (normal: 0.5 to 8.45 mcg/mL). His hospital course was complicated by oliguric renal failure requiring hemodialysis, metabolic encephalopathy, seizure activity, and mechanical ventilation for respiratory failure. The patient gradually improved with complete resolution of symptoms within 10 days; no permanent sequelae developed (Daul & Beuhler, 2011).
    B) CASE REPORT: A 16-year-old girl developed epigastric discomfort, sensation of warmth, chills and intermittent rash (diffuse, red, flat, and coalescent), primarily affecting her scalp, face, and legs. She admitted to seeing a nutritionist who had put her on megavitamin therapy containing 330 mg (more than 25 times the recommended daily allowance for a teenager) of niacin daily. Symptoms resolved upon discontinuation of the megavitamin therapy (Menna, 1993).
    C) CASE REPORTS: Two teenagers developed hepatotoxicity and acidosis after ingestion of 5 and 6 g of sustained-release niacin over a 48-hour period (Paopairochanakorn et al, 2001).
    D) CASE REPORT: After ingesting 11,000 mg of niacin within a 12-hour period, a 56-year-old man developed severe hypotension (BP 58/40 mmHg) in the absence of cutaneous flushing. Despite IV infusion of over 4 L of normal saline, he remained hypotensive, requiring IV dopamine infusion for 12 hours. Serum niacin levels at 48 and 96 hours postingestion were 8.2 mcg/mL and 5.6 mcg/mL, respectively (Mularski et al, 2006).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) After ingesting 11,000 mg of niacin within a 12-hour period, a 56-year-old man developed severe hypotension in the absence of cutaneous flushing. Serum niacin levels at 48 and 96 hours post-ingestion were 8.2 mcg/mL and 5.6 mcg/mL, respectively (Mularski et al, 2006).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) NIACIN
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 358 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)MOUSE:
    a) 3720 mg/kg (RTECS, 2002)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 3500 mg/kg (RTECS, 2002)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 730 mg/kg (RTECS, 2002)
    5) LD50- (ORAL)RAT:
    a) DOSE: 7 gm/kg (RTECS, 2002)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 5 gm/kg (RTECS, 2002)
    B) NIACINAMIDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 2050 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)MOUSE:
    a) 2500 mg/kg (RTECS, 2002)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 2 gm/kg (RTECS, 2002)
    4) LD50- (ORAL)RAT:
    a) 3500 mg/kg (RTECS, 2002)
    5) LD50- (SUBCUTANEOUS)RAT:
    a) 1680 mg/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) NIACINAMIDE (NICOTINAMIDE) is the amide metabolite of niacin (nicotinic acid). Both niacinamide and niacin are water-soluble, B complex vitamins (Gilman et al, 1985; AMA, 1986).
    B) Niacinamide is formed in vivo from metabolism of niacin. Niacinamide is an essential precursor of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are the physiologically active forms of niacin. Serving as coenzymes for several dehydrogenases, NAD and NADP are functional groups of electron-transfer agents active in cellular respiration, glycolysis, and lipid synthesis (AMA, 1986; Figge et al, 1988).
    C) NIACIN: Several possible modes of action have been proposed including, inhibition of hepatic synthesis of lipoproteins containing apolipoprotein B-100 (Grundy, 1990); promotion of lipoprotein lipase activity (Odetti et al, 1984), and reduction of free fatty acid mobilization from adipose tissue with an increase in fecal output of sterols (Nash, 1983).
    D) As B complex vitamins, niacin and niacinamide have identical physiological effects (Gilman et al, 1985). However, these vitamins differ in some of their actions. Niacin produces peripheral vasodilation and flushing, an effect not generally shared with niacinamide (Gilman et al, 1985) (Zackheim et al, 1981) (Ranchoff & Tomecki, 1986; Hoffer, 1971); however, flushing has been observed with niacinamide in some studies (Zackheim, 1978) (Zackheim et al, 1981) suggesting the vitamin may not be totally devoid of vasodilating activity. The overall incidence and severity of adverse effects, including hepatotoxicity, gastrointestinal complaints, and hyperuricemia, may be less with niacinamide as compared to niacin (Hoffer, 1969; Handfield-Jones et al, 1988; Ranchoff & Tomecki, 1986) Zackheim et al, 1981; (Gilman et al, 1985).
    E) Niacin can also reduce serum levels of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), while at the same time increasing high-density lipoprotein (HDL) levels, and is used as an agent of choice in the treatment of hyperlipidemia (Figge et al, 1988; AMA, 1986). In contrast, niacinamide has lacked this effect in most studies (Altschul et al, 1955; Parsons & Finn, 1957; Figge et al, 1988), although some evidence of lipid-lowering activity has been observed with long-term administration, possibly due to conversion of niacinamide to niacin (Carlson et al, 1972; Figge et al, 1988).
    F) Acipimox is a derivative of niacin. However, unlike niacin, acipimox does not undergo significant metabolism and is mostly excreted in the urine unchanged. Possibly due to this lack of metabolism, acipimox has a longer duration of action and greater hypolipidemic activity than niacin. In addition, it is better tolerated than niacin, with a lower incidence of adverse effects such as flushing, which can be severe with niacin. Its mechanism of action is postulated to be similar to that of niacin, possibly involving interference with enzymes regulating lipolysis. Acipimox is approximately 20 times more potent than niacin as an inhibitor of fasting-induced lipolysis, is longer-acting, and causes less serum free fatty acid rebound than niacin (Fuccella et al, 1980; Musatti et al, 1981).

Physicochemical

Physical Characteristics

    A) NIACIN: White crystals or crystalline powder, very soluble in water (Prod Info NIASPAN(R) extended-release oral tablets, 2010).

Molecular Weight

    A) NIACIN: 123.1 (Prod Info NIASPAN(R) extended-release oral tablets, 2010)

References

General Bibliography

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    70) Product Information: ADVICOR(R) oral tablets, niacin extended-release lovastatin oral tablets. Kos Pharmaceuticals, Cranbury, NJ, 2007.
    71) Product Information: Advicor(R) oral extended-release tablets, niacin lovastatin oral extended-release tablets. Abbott Laboratories (per FDA), North Chicago, IL, 2012.
    72) Product Information: Advicor(R), niacin extended-release/lovastatin tablets. Kos Pharmaceuticals, Inc, Miami, FL, 2001.
    73) Product Information: NIACOR(R) oral tablet, niacin oral tablet. Upsher-Smith Laboratories, Inc, Minneapolis, MN, 2005.
    74) Product Information: NIACOR(R) oral tablets, niacin oral tablets. Upsher-Smith Laboratories,Inc, Minneapolis, MN, 2000a.
    75) Product Information: NIACOR(R) oral tablets, niacin oral tablets. Upsher-Smith Laboratories, Inc. (per DailyMed), Minneapolis, MN, 2000.
    76) Product Information: NIASPAN(R) extended-release oral tablets, niacin extended-release oral tablets. Abbott Laboratories, North Chicago, IL, 2010.
    77) Product Information: NIASPAN(R) oral extended-release tablets, niacin oral extended-release tablets. AbbVie Inc. (per FDA), North Chicago, IL, 2015.
    78) Product Information: NIASPAN(R), niacin extended-release tablets. Kos Pharmaceuticals, Inc, Cranbury, NJ, 2005.
    79) Product Information: Niaspan(R) niacin extended-release tablets. Kos Pharmaceuticals, Inc., Miami, FL, 2003.
    80) Product Information: Niaspan(R), niacin, extended release tablet. Kos Pharmaceuticals, Miami, FL, 1999.
    81) Product Information: SIMCOR(R) extended-release oral tablets, simivastatin niacin extended-release oral tablets. Abbott Laboratories, Columbus, OH, 2008.
    82) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    83) Product Information: niacin oral tablets, niacin oral tablets. Mason Vitamins,Inc, Miami Lakes, FL, 2007.
    84) Product Information: niacin oral tablets, niacin oral tablets. Nature's Bounty, Bohemia, NY, 2005.
    85) Product Information: niacin oral tablets, niacin oral tablets. Nature's Bounty, Bohemia, NY, 2005a.
    86) Product Information: niacinamide oral tablets, niacinamide oral tablets. Nature's Bounty, Bohemia, NY, 2000.
    87) Product Information: niacinamide oral tablets, niacinamide oral tablets. Rugby Laboratories,Inc, Duluth, GA, 2006.
    88) Product Information: niacinamide oral tablets, niacinamide oral tablets. Rx Vitamins,Inc, Larchmont, NY, 2006a.
    89) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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