Nicotinamide

(rINN)
Nicotinamide Chemical formula
Synonyms: Niacinamide; Nicotinamida; Nicotinamidum; Nicotinic Acid Amide; Nicotylamide; Nikotiiniamidi; Nikotinamid; Nikotinamidas; Nikotynamid; Vitamin B 3 ; Vitamin PP. Pyridine-3-carboxamide.
Cyrillic synonym: Никотинамид.

💊 Chemical information

Chemical formula: C6H6N2O = 122.1.
CAS — 98-92-0.
ATC — A11HA01.
ATC Vet — QA11HA01.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, US, and Viet.

Ph. Eur. 6.2

(Nicotinamide). A white or almost white, crystalline powder or colourless crystals. Freely soluble in water and in dehydrated alcohol. A 5% solution in water has a pH of 6.0 to 7.5.

USP 31

(Niacinamide). A white crystalline powder, odourless or practically so. Soluble 1 in 1.5 of water, 1 in 10 of boiling water, and 1 in 5.5 of alcohol; soluble in glycerol. Its solutions are neutral to litmus. Store in airtight containers.

💊 Adverse Effects and Treatment

Nicotinic acid has a vasodilator action and when given by mouth or by injection in therapeutic doses it may cause flushing, a sensation of heat, faintness, and a pounding in the head. Flushing may be accompanied by dizziness, tachycardia, palpitations, dyspnoea, sweating, chills, or oedema. These symptoms are transient and various strategies have been proposed to reduce them (see Incidence of Adverse Effects, below). Nicotinamide does not have a vasodilator action. Other adverse effects that have been reported, especially after high doses of nicotinic acid, include dryness of the skin, pruritus, hyperpigmentation, cramps, diarrhoea, nausea and vomiting, anorexia, activation of peptic ulcer, amblyopia, jaundice and impairment of liver function, decrease in glucose tolerance, hyperglycaemia, and hyperuricaemia. Most of these effects subside on withdrawal of the drug. Hypophosphataemia, a reduction in platelet counts, and prolongation of prothrombin time have also been reported. Insomnia, myalgia, hypotension, and rhinitis may occur rarely. Topical nicotinamide may cause dryness of the skin and, less frequently, pruritus, erythema, burning sensation, and irritation. Frequency of application should be reduced if these effects occur.
1. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol 2007; 99 (suppl 1): S22–S31.

Incidence of adverse effects.

Nicotinic acid produces frequent adverse effects, but they are not usually serious, tend to decrease with time, and some can be minimised by following appropriate instructions for use.1,2 Dermal and gastrointestinal reactions are most common. Truncal and facial flushing are reported in 90 to 100% of treated patients in large clinical trials; they appear to be prostaglandin-mediated and can be reduced with aspirin 75 mg or 325 mg given shortly before the nicotinic acid, or simply by giving nicotinic acid with food, and by starting therapy with a low dose and gradually increasing this. Flushing may be less common with modified-release formulations.2
1. Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs. Med Toxicol 1987; 2: 10–32
2. American Society of Health-System Pharmacists. ASHP therapeutic position statement on the safe use of niacin in the management of dyslipidemias. Am J Health-Syst Pharm 1997; 54: 2815–19.

Effects on the eyes.

Retrospective survey of hyperlipidaemic patients suggested that dry eyes (sicca syndromes), blurred vision, and swollen eyelids might be associated with nicotinic acid therapy in some patients.1 The effects appeared to be dose-related and reversible. In 2 patients treatment was stopped because of symptoms suggestive of cystoid macular oedema. Other cases of nicotinic acid maculopathy have been reported.2,3
1. Fraunfelder FW, et al. Adverse ocular effects associated with niacin therapy. Br J Ophthalmol 1995; 79: 54–6
2. Callanan D, et al. Macular edema associated with nicotinic acid (niacin). JAMA 1998; 279: 1702
3. Spirn MJ, et al. Optical coherence tomography findings in nicotinic acid maculopathy. Am J Ophthalmol 2003; 135: 913–14.

Effects on glucose tolerance.

Nicotinic acid can reduce glucose tolerance, and this may be problematic in patients with diabetes mellitus,1,2 although it has been investigated in the prevention of diabetes mellitus (see below).
1. American Society of Health-System Pharmacists. ASHP therapeutic position statement on the safe use of niacin in the management of dyslipidemias. Am J Health-Syst Pharm 1997; 54: 2815–19
2. Kreisberg RA. Niacin: a therapeutic dilemma—"one man’s drink is another’s poison". Am J Med 1994; 97: 313–16.

Effects on the liver.

Hepatotoxicity may occur with nicotinic acid.1-6 Significant elevations of liver enzymes are occasionally seen with nicotinic acid therapy. They are more common in patients given large dosage increases over short periods of time, and in patients treated with modified-release formulations. It has been suggested7 that since effects on liver function may in some instances lead to hepatic failure and are more common with modified-release dosage forms the use of crystalline immediate-release preparations should be preferred, a view shared by other commentators.8 However, although studies appear to confirm a more frequent association of hepatotoxicity with modified-release dosage forms4,9,10 it should be borne in mind that these effects can also occur with the immediate-release preparations, especially at high doses. Some manufacturers of modified-release preparations have stated that cases of severe hepatotoxicity, including fulminant hepatic necrosis, have occurred when patients have substituted modified-release dosage forms for immediaterelease crystalline preparations at equivalent doses. There is also a suggestion that not all modified-release preparations are alike in their effects.11
1. Henkin Y, et al. Rechallenge with crystalline niacin after druginduced hepatitis from sustained-release niacin. JAMA 1990; 264: 241–3
2. Hodis HN. Acute hepatic failure associated with the use of lowdose sustained-release niacin. JAMA 1990; 264: 181
3. Etchason JA, et al. Niacin-induced hepatitis: a potential side effect with low-dose time-release niacin. Mayo Clin Proc 1991; 66: 23–8
4. Rader JI, et al. Hepatic toxicity of unmodified and time-release preparations of niacin. Am J Med 1992; 92: 77–81
5. Coppola A, et al. Niacin-induced hepatotoxicity: unusual presentations. South Med J 1994; 87: 30–2
6. Gavilán JC, et al. Hepatitis inducida por niacina. Med Clin (Barc) 2002; 118: 558
7. Palumbo PJ. Rediscovery of crystalline niacin. Mayo Clin Proc 1991; 66: 112–13
8. Kreisberg RA. Niacin: a therapeutic dilemma—"one man’s drink is another’s poison". Am J Med 1994; 97: 313–16
9. McKenney JM, et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994; 271: 672–7
10. Gray DR, et al. Efficacy and safety of controlled-release niacin in dyslipoproteinemic veterans. Ann Intern Med 1994; 121: 252–8
11. Lavie CJ, Milani RV. Safety and side-effects of sustained-release niacin. JAMA 1994; 272: 513–14.

Effects on the muscles.

Myopathy has been noted with nicotinic acid.1,2 Rhabdomyolysis has occurred when nicotinic acid was given with lovastatin.
1. Litin SC, Anderson CF. Nicotinic-acid associated myopathy: a report of three cases. Am J Med 1989; 86: 481–3
2. Gharavi AG, et al. Niacin-induced myopathy. Am J Cardiol 1994; 74: 841–2.

Hyperuricaemia.

Nicotinic acid decreases urinary excretion of uric acid, which may result in elevation of serum uric acid and exacerbation of pre-existing gout.1
1. American Society of Health-System Pharmacists. ASHP therapeutic position statement on the safe use of niacin in the management of dyslipidemias. Am J Health-Syst Pharm 1997; 54: 2815–19.

💊 Precautions

Nicotinic acid should be given cautiously to patients with a history of peptic ulcer disease, and to those with diabetes mellitus, gout, or hepatic impairment. Modified-release preparations should not be substituted for equivalent doses of immediate-release crystalline nicotinic acid preparations, as cases of severe hepatotoxicity, including fulminant hepatic necrosis, have occurred. Liver function tests and plasma glucose should be frequently monitored.

💊 Interactions

There may be an increased risk of myopathy or rhabdomyolysis when nicotinic acid is used with statins. Nicotinic acid may increase the requirements for insulin or oral hypoglycaemics. Aspirin may reduce the clearance of nicotinic acid. In vitro studies suggest that colestipol and colestyramine may reduce the availability of nicotinic acid, and some licensed product information recommends an interval of at least 4 to 6 hours between giving nicotinic acid and bile-acid binding resins.

Antiepileptics.

For the effect of nicotinamide on carbamazepine, see Vitamins.

Nicotine.

A patient started to have flushing and dizziness after her usual doses of nicotinic acid when transdermal nicotine patches were added to her therapy.1 She had experienced such reactions 3 years previously on starting nicotinic acid therapy, but not since, and it was suggested that on this occasion an interaction might have been responsible.
1. Rockwell KA. Potential interaction between niacin and transdermal nicotine. Ann Pharmacother 1993; 27: 1283–4.

💊 Pharmacokinetics

Nicotinic acid and nicotinamide are readily absorbed from the gastrointestinal tract after oral doses and widely distributed in the body tissues. Nicotinic acid appears in breast milk. The main route of metabolism is their conversion to N-methylnicotinamide and the 2pyridone and 4-pyridone derivatives; nicotinuric acid is also formed. Small amounts of nicotinic acid and nicotinamide are excreted unchanged in urine after therapeutic doses; however the amount excreted unchanged is increased with larger doses.
1. Pieper JA. Overview of niacin formulations: differences in pharmacokinetics, efficacy, and safety. Am J Health-Syst Pharm 2003; 60 (Suppl 2): S9–14.

💊 Human Requirements

The daily human requirement of nicotinic acid, though not definitely known, is probably about 15 to 20 mg. Yeast, meat, fish, potatoes, legumes, and wholemeal cereals are good sources of nicotinic acid and nicotinamide. However they may be present in a bound, unabsorbable form in cereals, especially maize. Nicotinic acid can also be obtained from the conversion of tryptophan in the body, 60 mg of dietary tryptophan being considered equivalent to 1 mg of dietary nicotinic acid, so requirements are influenced by dietary protein intake and if protein intake is adequate there is little need for any preformed vitamin in the diet. There is generally little loss of nicotinic acid from foods during cooking.

UK and US recommended dietary intake.

In the UK dietary reference values have been published for nicotinic acid1 and in the USA recommended dietary allowances (RDAs) have been set.2 In the UK the reference nutrient intake (RNI) is 6.6 mg niacin equivalent per 1000 kcal daily and the estimated average requirement (EAR) is 5.5 mg niacin equivalent per 1000 kcal daily for adult males and females. One niacin equivalent is equal to 1 mg of dietary nicotinic acid or 60 mg of dietary tryptophan. In the US the RDAs are also expressed in niacin equivalents and are 16 mg daily for adult males and 14 mg daily for adult females; the EAR is 12 mg daily in males and 11 mg daily in females. The tolerable upper intake level for adults is 35 mg daily.2
1. DoH. Dietary reference values for food energy and nutrients for the United Kingdom: report of the panel on dietary reference values of the committee on medical aspects of food policy. Report on health and social subject
41. London: HMSO, 1991
2. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board. Dietary Reference Intakes for thiamin, riboflavin, niacin, vitamin B , folate, vitamin B , pantothenic acid, biotin, and choline. Washington, DC: National Academy Press, 2000. Also available at: http://www.nap.edu/openbook.php?isbn=0309065542 (accessed 21/07/08)

💊 Uses and Administration

Nicotinic acid and nicotinamide, the form that occurs naturally in the body, are water-soluble vitamin B substances that are converted to nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes are involved in electron transfer reactions in the respiratory chain. Nicotinic acid deficiency develops when the dietary intake is inadequate. Deficiency leads to the development of a syndrome known as pellagra, characterised by skin lesions, especially on areas exposed to sunlight, with hyperpigmentation and hyperkeratinisation. Other symptoms include diarrhoea, abdominal pain, glossitis, stomatitis, loss of appetite, headache, lethargy, and mental and neurological disturbances. Nicotinic acid deficiency may occur with other vitamin B-complex deficiency states, for example in alcoholism. Nicotinic acid and nicotinamide are used in the treatment and prevention of nicotinic acid deficiency. Nicotinamide is preferred as it does not cause vasodilatation. They are usually given orally, the preferred route, but may also be given by the intramuscular route or by slow intravenous injection. Doses of up to 500 mg daily (of either compound) in divided doses have been recommended. Nicotinic acid has been used for its vasodilator action in the treatment of a variety of disorders; its value is not considered to be established. In high doses, nicotinic acid has beneficial effects on blood lipid profiles, and has been used, with dietary modification and often with other lipid regulating drugs, in hyperlipidaemias (see below). For the immediate-release preparations, up to 600 mg daily in 3 divided oral doses has been given initially, gradually increased over 2 to 4 weeks to doses of up to 6 g daily; adverse effects may be a limiting factor. Alternatively, initial doses of 375 or 500 mg at night have been given as a modified-release preparation and gradually increased according to response to a maintenance dose of 1 to 2 g at bedtime. The daily dose should not be increased by more than 500 mg in any 4-week period. A combination preparation containing nicotinic acid with laropiprant, a prostaglandin D 2 antagonist that inhibits nicotinic acid-induced flushing, may also be used. Topical nicotinamide is used in the treatment of mild to moderate inflammatory acne (see below), typically as a 4% gel applied twice daily. Nicotinamide has been shown to inhibit the destruction of pancreatic beta cells in vitro and is therefore being investigated in the prevention and treatment of type 1
diabetes mellitus (see below).

Acne.

Topical nicotinamide may be used in the treatment of inflammatory acne; nicotinamide 4% was as effective as clindamycin 1% when applied topically twice daily for 8 weeks.1
1. Shalita AR, et al. Topical nicotinamide compared with clindamycin gel in the treatment of inflammatory acne vulgaris. Int J Dermatol 1995; 34: 434–7.

Diabetes mellitus.

Nicotinic acid can affect glucose tolerance and should be used with care in established diabetes (see Effects on Glucose Tolerance, above). However, the drug has been used successfully in patients with diabetes. Nicotinamide has been reported to induce remission in patients with newly diagnosed type 1 diabetes mellitus, and may delay the onset of disease.1,2 However, a randomised trial found modified-release nicotinamide at 1.2 g/m2 daily (to a maximum of 3 g daily) to be ineffective in preventing the onset of diabetes mellitus in first-degree relatives of patients with the disease.3 Nicotinic acid can also raise high-density lipoprotein (HDL)-cholesterol concentrations (see below);4,5 changes in glucose tolerance were mild enough for the drug to be considered as an alternative to statins and fibrates in diabetic patients.
1. Elliott RB, Chase HP. Prevention or delay of type 1 (insulin-dependent) diabetes mellitus in children using nicotinamide. Diabetologia 1991; 34: 362–5
2. Pozzilli P, et al. Meta-analysis of nicotinamide treatment in patients with recent-onset IDDM. Diabetes Care 1996; 19: 1357–63
3. European Nicotinamide Diabetes Intervention Trial Group. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type I diabetes. Lancet 2004; 363: 925–31
4. Elam MB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. JAMA 2000; 284: 1263–70
5. Grundy SM, et al. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of Niaspan trial. Arch Intern Med 2002; 162: 1568–76.

Hyperlipidaemias.

The first-line treatment for hyperlipidaemias remains dietary and lifestyle modification; where this fails, drug therapy may be considered. Nicotinic acid is reported to have a favourable effect on blood-lipid profiles, raising high-density lipoprotein (HDL)-cholesterol and lowering lowdensity lipoprotein (LDL)-cholesterol.1-3 Nicotinic acid is used particularly in familial hypertriglyceridaemia, or in familial combined hyperlipidaemia when both triglyceride and cholesterol concentrations are similarly elevated. Nicotinic acid was less effective than lovastatin at reducing LDL-cholesterol in patients with primary hypercholesterolaemia, but more effective at increasing HDL-cholesterol; lovastatin was better tolerated.4 A combination of nicotinic acid with lovastatin was found to be comparable to atorvastatin and more effective than simvastatin in reducing LDL-cholesterol, and more effective than either atorvastatin or simvastatin in increasing HDL-cholesterol, in a study of patients with dyslipidaemia.5 Some have recommended that nicotinic acid be substituted for a statin to lower LDL-cholesterol when patients cannot tolerate a statin.2 Combination therapy is recommended when the reduction in LDL-cholesterol is insufficient with statin monotherapy,2,6 or when raising HDL-cholesterol would be beneficial,7-9 as in patients with type 2 diabetes mellitus, or the metabolic syndrome.8 The risk of muscle toxicity with this combination is not considered to be significantly different to that with statin monotherapy.7
1. McKenney JM, et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994; 271: 672–7
2. McKenney J. Niacin for dyslipidemia: considerations in product selection. Am J Health-Syst Pharm 2003; 60: 995–1005
3. McCormack PL, Keating GM. Prolonged-release nicotinic acid: a review of its use in the treatment of dyslipidaemia. Drugs 2005; 65: 2719–40
4. Illingworth DR, et al. Comparative effects of lovastatin and niacin in primary hypercholesterolemia: a prospective trial. Arch Intern Med 1994; 154: 1586–95
5. Bays HE, et al. Comparison of once-daily, Niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (The Advicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). Am J Cardiol 2003; 91: 667–72
6. Miller M. Niacin as a component of combination therapy for dyslipidemia. Mayo Clin Proc 2003; 78: 735–42
7. McKenney J. New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med 2004; 164: 697–705
8. Chapman MJ, et al. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid— a position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 2004; 20: 1253–68
9. Yim BT, Chong PH. Niacin-ER and lovastatin treatment of hypercholesterolemia and mixed dyslipidemia. Ann Pharmacother 2003; 37: 106–15.

Pemphigus.

Oral treatment with nicotinamide and a tetracycline1-6 has controlled lesions in pemphigus and pemphigoid, including persistent pemphigoid gestationis,5 and ocular cicatricial pemphigoid.6
1. Sawai T, et al. Pemphigus vegetans with oesophageal involvement: successful treatment with minocycline and nicotinamide. Br J Dermatol 1995; 132: 668–70
2. Kolbach DN, et al. Bullous pemphigoid successfully controlled by tetracycline and nicotinamide. Br J Dermatol 1995; 133: 88–90
3. Reiche L, et al. Combination therapy with nicotinamide and tetracyclines for cicatricial pemphigoid: further support for its efficacy. Clin Exp Dermatol 1998; 23: 254–7
4. Goon ATJ, et al. Tetracycline and nicotinamide for the treatment of bullous pemphigoid: our experience in Singapore. Singapore Med J 2000; 41: 327–30
5. Amato L, et al. Successful treatment with doxycycline and nicotinamide of two cases of persistent pemphigoid gestationis. J Dermatol Treat 2002; 13: 143–6
6. Dragan L, et al. Tetracycline and niacinamide: treatment alternatives in ocular cicatricial pemphigoid. Cutis 1999; 63: 181–3.

💊 Preparations

BP 2008: Nicotinamide Tablets; Nicotinic Acid Tablets; Vitamins B and C Injection; BPC 1973: Compound Vitamin B Tablets; Strong Compound Vitamin B Ta b l e t s ; USP 31: Niacin Injection; Niacin Tablets; Niacinamide Injection; Niacinamide Tablets.

Proprietary Preparations

Arg.: NB-3; Niaspan; Nicozinc; Austria: Direktan; Nicovitol; Belg.: Ucemine PP; Braz.: Papuless; Canad.: Niaspan; Chile: Cotina; Niacex; Niaspan; Vectidan†; Fin.: Niaspan; Fr.: Niaspan; Nicobion; Ger.: Niaspan; Nicobion; Hong Kong: Niaspan; India: Nialip; Indon.: Niacef; Niaspan; Irl.: Niaspan; Nicam; Mex.: Hipocol; Nacro; Pepevit; Neth.: Niaspan; Philipp.: Niaspan; Port.: Niaspan; Singapore: Niaspan; Swed.: Niaspan; Nicangin; Thai.: Nicotabs; UK: Freederm; Niaspan; Nicam; USA: Endur-acin; Niaspan; Nicotinex†; Slo-Niacin; Venez.: Niaspan. Multi-ingredient: Arg.: Antikatarata†; Centella Asiatica Compuesta; IP6; Nicozinc; Parencias†; Austral.: Bioglan Cirflo†; Chilblain Formula†; Gingo A†; Prochol†; Silybum Complex†; Austria: Beneuran Vit B-Komplex†; Diligan; Pertrombon; Spasmocor; Belg.: Trihistalex; Braz.: Gaba†; Nicopaverina B6†; Nicopaverina†; Canad.: PML Crono†; Chile: Cicapost; Perfungol; Ureadin Forte; Ureadin Rx PS; Ureadin Rx RD; Fin.: Neurovitan; Vertipam; Fr.: TTD-B -B ; Vita-Dermacide; Ger.: Eukalisan N; Hepagrisevit Forte-N†; MerSol†; Peteha†; Telbibur N†; Hung.: Paniverin; India: Diligan; HepaMerz; Nutrozyme; Sioneuron; Unienzyme; Indon.: Biocholes; Cereton; Kitoles; Sotens; Irl.: Effaclar AI; Israel: Babyzim; Ital.: Emazian B12†; Emoantitossina†; Emopon; Epargriseovit; Fisioreve; Folepar B12; Fosforilasi; Neuroftal†; Novostatin; Solvobil; Vit-Porphyrin†; Mon.: Monasens; Philipp.: Jetepar; Pol.: Dernilan; Port.: Diligan†; Ureadin Forte; Rus.: Lidevine (Лидевин); Oftan Catachrom (Офтан Катахром); S.Afr.: Cosaldon†; Singapore: Erase; Spain: Depurativo Richelet; Euzymina Lisina I; Euzymina Lisina II; Vitaphakol; Swed.: Theranyl†; Thai.: B-100 Complex; Turk.: Epargriseovit; UK: Crampex; Quiet Life; S.P.H.P.; USA: Advicor; Simcor.
Published January 19, 2019.