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NIACINAMIDE DRUGDEX® Evaluations OVERVIEW 1) Class a) This drug is a member of the following class(es): Antiacne Antihyperlipidemic Nicotinic Acid (class) Nutritive Agent Vitamin B 2) Dosing Information a) Adult 1) Pellagra a) ORAL, 300-500 mg/day, divided into 2-3 doses b) IM, 50-100 mg/day in 5 or more divided doses c) IV, 25-100 mg every 2-3 hr, MAX 1g/day b) Pediatric 1) Pellagra a) ORAL, 100-300 mg/day, divided into 2-3 doses 3) Contraindications a) active peptic ulcer disease b) hypersensitivity to niacinamide products c) liver disease 4) Serious Adverse Effects a) Hepatotoxicity 5) Clinical Applications a) FDA Approved Indications 1) Pellagra DOSING INFORMATION Drug Properties A) Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product Index) B) Synonyms Niacinamide Niacinamide Ascorbate Nicotinamide Nicotinamide Ascorbate Nicotinic Acid Amide Adult Dosage Normal Dosage Intramuscular route 1) If given intramuscularly, the recommended dose for the acute treatment of pellagra is 50 to 100 milligrams daily, in 5 or more divided doses [12] . Intravenous route 1) The preferred parenteral route of administration of niacinamide is intravenous. For the acute treatment of PELLAGRA, the recommended intravenous dose is 25 to 100 milligrams every 2 to 3 hours (maximum dose = 1 gram daily). Oral administration and a well-balanced diet should be initiated as soon as possible [12] . 2) When given intravenously, niacinamide should be given slowly, with concentrations not exceeding 10 milligrams/milliliter. Alternatively, the dose may be diluted in 500 milliliters of normal saline and administered at a rate of 2 milligrams/minute [12] . Oral route Bullous pemphigoid a) Another small trial reported the successful treatment of BULLOUS PEMPHIGOID (N=16) with a combination regimen of oral OXYTETRACYCLINE (500 milligrams (mg) 4 times daily), oral niacinamide (400 mg 3 times daily), and topical 0.5% clobetasol propionate cream. Once lesions began to heal, the oral doses were tapered over several weeks and clobetasol was replaced with a moisturizing emollient (Hornshuh et al, 1997). Commonly used doses for BULLOUS PEMPHIGOID include 1 gram to 2 grams a day of TETRACYCLINE in combination with 1.2 grams to 2 grams a day of NIACINAMIDE for a duration of a few weeks to years (mean, 7 months). Within 1 to 2 weeks improvement may be noticed, however, adjunctive topical steroids may alleviate new lesions during the beginning of therapy. Up to 1 month of treatment may be needed before response occurs [18] . When treating extensive bullous pemphigoid, tapering-off over 1 to 2 months, may be necessary; a more rapid taper is possible if using topical steroids [18] . The oral route is preferred for the treatment of PELLAGRA. Recommended oral doses of niacinamide for the acute treatment of pellagra are 300 to 500 milligrams orally daily in divided doses. In patients with less severe deficiency, 50 to 100 milligrams daily can be given [12] . PERIPHERAL NEURITIS associated with thiamine deficiency does not respond to niacinamide, and thiamine replacement is indicated in these patients. Macrocytic anemia in pellagra patients may be related to folic acid deficiency; however, most clinicians recommend small doses of all B complex vitamins, as well as a well-balanced diet with adequate protein to provide tryptophan, as adjunctive therapy of pellagra [12] [19] . For MAINTENANCE THERAPY, preparations containing Recommended Dietary Allowances (RDA) of niacinamide, thiamine, riboflavin, and pyridoxine should be administered daily [12] . The Recommended Dietary Allowance (RDA) of niacinamide in adults is 13 to 19 milligrams/day. This amount exceeds the minimum requirement necessary to prevent deficiency. Oral doses of 10 to 20 milligrams daily are recommended for DIETARY SUPPLEMENTATION [12] . For individuals who consume few calories, such as the elderly, daily intake should not fall below 13 milligrams [19] . Larger amounts of niacinamide are needed during periods of increased metabolism, including pregnancy, lactation, prolonged infection, hyperthyroidism, and burns [12] . Pediatric Dosage Normal Dosage Oral route 1) The oral route is preferred for the treatment of PELLAGRA. The recommended dose of niacinamide for the acute treatment of pellagra in children, is 100 to 300 milligrams daily in divided doses [12] . 2) PERIPHERAL NEURITIS associated with thiamine deficiency does not respond to niacinamide, and thiamine replacement is indicated in these patients. Macrocytic anemia in pellagra patients may be related to folic acid deficiency; however, most clinicians recommend small doses of all B complex vitamins, as well as a well-balanced diet with adequate protein to provide tryptophan, as adjunctive therapy of pellagra [12] [19] . 3) The Recommended Dietary Allowance (RDA) of niacinamide in children is 9 to 16 milligrams/day. This amount exceeds the minimum requirement necessary to prevent deficiency [12] . 4) Larger amounts of niacinamide are needed during periods of increased metabolism, including prolonged infection, hyperthyroidism, and burns [12] . 5) The efficacy of niacinamide 250 milligrams/day orally in the treatment of HARTNUP DISEASE was reported in a 12-year-old boy presenting with pellagra and CEREBELLAR ATAXIA [13] . PHARMACOKINETICS Onset and Duration A) Onset 1) Initial Response a) Pellagra, oral: 24 hours [41] . Drug Concentration Levels A) Therapeutic Drug Concentration 1) Tumor radiosensitization, 700 nanomoles/milliliter [42] B) Time to Peak Concentration 1) Oral: 1 to 4 hours [42] C) Area Under the Curve 1) 20,000 nanomoles x hr/mL [42] ADME Distribution A) Distribution Sites 1) OTHER DISTRIBUTION SITES a) Placenta 1) Concentrations in the fetus and newborn are higher than in the mother [43] [44] . b) Tissues 1) Niacinamide is rapidly distributed to all tissues [41] . Metabolism A) Metabolism Sites and Kinetics 1) Liver a) NIACINAMIDE is formed in vivo from metabolism of NIACIN. NIACINAMIDE is further metabolized in the liver [45] [41] . B) Metabolites 1) Nicotinamide adenine dinucleotide (NAD), active [46] . 2) Nicotinamide adenine dinucleotide phosphate (NADP), active [46] . 3) N-methylniacinamide [45] [41] . 4) Nicotinuric acid, possibly active [45] . a) Nicotinuric acid (detoxification metabolite of NIACIN) is present in large amounts following oral administration of NIACIN [47] [45] but has been absent in the urine following repeated doses of NIACINAMIDE [45] . Nicotinuric acid reportedly possesses lipid-lowering activity [45] . Excretion A) Kidney 1) NIACINAMIDE and its metabolites are excreted in urine. With physiologic doses, only small amounts of unchanged NIACINAMIDE are recovered; however, unchanged NIACINAMIDE is the major urinary component after large oral doses [45] [41] . Elimination Half-life A) Parent Compound 1) Elimination half life: 10 hours [42] CAUTIONS Contraindications A) active peptic ulcer disease B) hypersensitivity to niacinamide products C) liver disease Precautions A) diabetes B) gallbladder disease C) gout D) history of liver disease E) history of peptic ulcer F) pregnancy/lactation Adverse Reactions Dermatologic Effects Flushing 1) Niacin produces peripheral vasodilation and flushing, an effect not generally shared with niacinamide [19] [24] [33] [34] . However, flushing has been observed rarely with niacinamide [25] [24] suggesting the vitamin may not be totally devoid of vasodilating activity. 2) In one study employing oral niacinamide, in combination with topical 6aminonicotinamide for psoriasis, flushing was observed in 3 of 204 patients. These 3 patients had received niacinamide in doses of 100 to 200 mg three times daily; reduction of the dose by 50% resulted in lessening or disappearance of flushing, enabling continuation of niacinamide therapy [24] . Rash 1) In contrast to niacin, skin reactions such as rash, hives, and facial erythema have been reported only rarely with niacinamide [24] [25] [23] . The acanthosis nigricans-like reactions observed with niacin have not been reported with niacinamide. 2) No cutaneous reactions were reported in 315 adult schizophrenic patients treated with niacinamide 3 to 12 g daily [30] . In another series, a severe skin rash was observed in only 1 of 982 schizophrenic patients receiving 3 to 6 g of niacinamide daily [23] . Endocrine/Metabolic Effects Hyperglycemia 1) In contrast to niacin, niacinamide has only rarely been associated with diabetogenic effects [27] [28] . Diabetes mellitus is not an absolute contraindication to the use of niacinamide; however, blood glucose monitoring is advisable during therapy [29] . 2) Improvement in diabetic control (reduced insulin requirements) was reported in an insulin-dependent diabetic following administration of niacinamide [28] . 3) In a series of 982 schizophrenic patients treated with high doses of niacinamide (up to 6 g daily), no changes in carbohydrate metabolism were observed [23] . Gastrointestinal Effects Diarrhea 1) Diarrhea has been reported during niacinamide therapy, particularly with large doses [24] [25] [23] [30] [26] [22] . The incidence of diarrhea is low, and possibly less than with high doses of niacin [24] [28] . Nausea 1) Nausea has been reported during niacinamide therapy, particularly with large doses [24] [25] [23] [30] [26] [22] . The incidence of nausea is low, and possibly less than with high doses of niacin [24] [28] . Vomiting 1) Vomiting has been reported during niacinamide therapy, particularly with large doses [24] [25] [23] [30] [26] [22] . However, the incidence of vomiting is low, and possibly less than with high doses of niacin [24] [28] . 2) 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 . A similar syndrome occurred with high dose niacin in this study. With both agents, flu-like gastrointestinal symptoms were mainly seen with doses exceeding 8 g daily [30] . Hepatic Effects Hepatotoxicity 1) Incidence: rare 2) 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 [24] [23] [31] . 3) The incidence of hepatotoxicity is probably very low. Only 1 of 6000 schizophrenic patients developed hepatic complications with high-dose niacinamide or niacin in 1 series [23] . Although direct comparative studies are lacking, hepatotoxicity appears to occur less frequently with niacinamide as compared to niacin [24] [32] [23] [28] ; this may be attributable to the lesser frequency of use of niacinamide. However, liver function tests should be monitored during niacinamide therapy, particularly with the use of higher doses. 4) Parenchymal-cell injury, portal fibrosis, and cholestasis were reported in a 35year-old male schizophrenic patient receiving niacinamide 9 g daily. Hepatotoxic effects were reversible and reproducible upon rechallenge [31] . Neurologic Effects Dizziness 1) Dizziness has been observed occasionally during niacinamide therapy [22] . Headache 1) Headache has occurred with administration of therapeutic or high doses of niacinamide (300 mg to 6 g daily) [23] [24] [25] [26] . However, the incidence of this adverse effect is low, even with large doses. In one series of 262 patients treated with niacinamide 3 g daily for schizophrenia, headache was observed in 4 [24] . In a further report, employing the use of niacinamide 100 to 3000 mg daily (in combination with topical 6-aminonicotinamide for psoriasis), headache was reported in only 1 of 204 patients [25] . Ophthalmic Effects Blurred vision 1) Blurring of the vision has been described rarely with niacinamide [24] . Teratogenicity/Effects in Pregnancy/Breastfeeding A) Teratogenicity/Effects in Pregnancy 1) Thomson Pregnancy Rating: Fetal risk is minimal. a) The weight of an adequate body of evidence suggests this drug poses minimal risk when used in pregnant women or women of childbearing potential. See Drug Consult reference: PREGNANCY RISK CATEGORIES 2) Crosses Placenta: Yes 3) Clinical Management a) Niacinamide is the amide metabolite of niacin. A number of prenatal vitamins contain niacinamide, and such supplements are indicated for the improvement of nutritional status prior to conception and throughout pregnancy [37] [38] . Nutritional supplement doses of vitamins and minerals are generally considered safe during pregnancy. Daily niacin requirements are increased during pregnancy to a dietary reference intake of 18 nanograms dietary niacin equivalents, an amount 28% over nonreproducing adult women [39] . B) Breastfeeding 1) Thomson Lactation Rating: Infant risk cannot be ruled out. a) Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding. 2) Clinical Management a) There is insufficient data in regards to nursing while on niacinamide and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Until additional data are available, caution should be exercised with the use of niacinamide in women who breastfeed their infants. 3) Literature Reports a) Niacinamide is probably excreted in breast milk, as is niacin [40] . Drug Interactions Drug-Drug Combinations Carbamazepine 1) Interaction Effect: an increased risk of carbamazepine toxicity (ataxia, nystagmus, diplopia, headache, vomiting, apnea, seizures, coma) 2) Summary: Two case reports describe a decrease in carbamazepine clearance when niacinamide was added to therapy. The decrease seen in the carbamazepine clearance correlated highly with increasing niacinamide doses [36] . 3) Severity: moderate 4) Onset: delayed 5) Substantiation: probable 6) Clinical Management: Monitor carbamazepine plasma levels in patients receiving niacinamide concomitantly. Adjust carbamazepine doses accordingly. 7) Probable Mechanism: inhibition of cytochrome P450 enzymes by niacinamide 8) Literature Reports a) Carbamazepine concentration increased in two epileptic patients after the addition of niacinamide. Both patients were also receiving primidone therapy, and niacinamide was added to decrease the conversion of primidone to phenobarbital. Patient 1, a 23-month old male receiving carbamazepine 72.7 mg/kg/day, had a carbamazepine clearance of 11.6 L/kg/day prior to niacinamide treatment, and the carbamazepine clearance decreased to 2.16 L/kg/day by the time the niacinamide dose had been titrated up to 178 mg/kg/day. In patient 2, a 10-year old male, the carbamazepine clearance decreased from 8.0 L/kg/day before niacinamide therapy to 3.37 L/kg/day when the niacinamide dose was 60 mg/kg/day. It was suspected that niacinamide inhibited the cytochrome P450 metabolism of carbamazepine [35] . Intravenous Admixtures Drugs Cephaloridine 1) Incompatible a) Cephaloridine (250 mg/L niacinamide 1 g/L in sterile distilled water exhibited significant antibiotic activity reduction in 1 hour at 25 degrees C) [71] b) Niacinamide (1 g/L with cephaloridine 250 mg/L in sterile distilled water exhibited significant antibiotic activity reduction in 1 hour at 25 degrees C) [72] Solutions ALKALINE SOLUTIONS 1) Incompatible a) Alkaline solutions reported to cause decomposition of nicotinamide; conditions not specified [73] TOTAL PARENTERAL NUTRITION 1) Compatible a) Nicotinamide as a component of a multivitamin solution with total parenteral nutrition, no significant degradation of nicotinamide reported when the admixture was stored for 96 hours at 2 to 8 degrees C in darkness in ethylene vinyl acetate - EVA - containers; specific composition of total parenteral solution described below [74] : Intralipid(R) 20% Vitalipid(R) N Adult Soluvit(R) N (multivitamin solution) Vamin(R) glucose Glucose 30% Addamel(R) electrolytes and trace elements Addiphos(R) phosphate solution Addex(R) sodium chloride solution Addex(R) magnesium solution Potassium acetate (2.5 mM/mL) Zinc Acetate (10 micromole/mL) CLINICAL APPLICATIONS Monitoring Parameters 500 mL 5 mL one-half ampule 1000 mL 500 mL 5 mL 5 mL 23 mL 4.5 mL 37 mL 5 mL A) Therapeutic 1) Physical Findings a) In patients with pellagra, rapid resolution of symptoms of tongue swelling, oral infections, gastrointestinal symptoms, delayed wound healing, and mental symptoms are indicative of a therapeutic response to niacinamide. B) Toxic 1) Laboratory Parameters a) Liver function tests, blood glucose levels, and serum uric acid levels should be monitored periodically during therapy. Patient Instructions A) Niacinamide (By mouth) Niacinamide Lowers cholesterol and triglyceride levels in your blood. This medicine is a vitamin (B3). When This Medicine Should Not Be Used: You should not use this medicine if you have had an allergic reaction to niacinamide (niacin). You may not be able to use this medicine if you have severe liver disease, ulcers, or if you have certain bleeding problems. How to Use This Medicine: Tablet, Capsule, Long Acting Tablet Your doctor will tell you how much of this medicine to use and how often. Your dose may need to be changed several times in order to find out what works best for you. Do not use more medicine or use it more often than your doctor tells you to.Carefully follow your doctor's instructions about any special diet or exercise program. It is best to take this medicine after your last meal of the day. Swallow the extended-release tablet whole. Do not crush, break, or chew it. If a Dose is Missed: If you miss a dose or forget to use your medicine, use it as soon as you can. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up for a missed dose. How to Store and Dispose of This Medicine: Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Ask your pharmacist, doctor, or health caregiver about the best way to dispose of any outdated medicine or medicine no longer needed. Keep all medicine away from children and never share your medicine with anyone. Drugs and Foods to Avoid: Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products. Make sure your doctor knows if you are using another medicine to lower cholesterol such as lovastatin, Lescol®, Lipitor®, Pravachol®, or Zocor®. Tell your doctor if you are using aspirin, vitamin supplements, or a nitrate medicine such as nitroglycerin or isosorbide. Make sure your doctor knows if you are also using medicine to lower blood pressure. Some blood pressure medicines are atenolol, diltiazem, nifedipine, propranolol, verapamil, Cartia®, Coreg®, Lotrel®, Norvasc®, Plendil®, Tiazac®, and Toprol®. Make sure your doctor knows if you drink alcohol on a daily or regular basis. Warnings While Using This Medicine: Make sure your doctor knows if you are pregnant or breast feeding, or if you have diabetes. Tell your doctor if you have angina (chest pain) or low blood pressure. Your doctor will need to know if you have a history of liver or gallbladder disease, ulcers, gout, or jaundice (skin or eyes turn yellow). Follow your doctor's instructions carefully if you are switching to this medicine from another form of niacinamide. The dose may be different if you switch from the regular tablet to the extended-release tablet. Your doctor will need to check your blood at regular visits while you are using this medicine. Be sure to keep all appointments. Make sure any doctor or dentist who treats you knows that you are using this medicine. This medicine may affect the results of certain medical tests. This medicine may cause a warmth or redness in your face, neck, arms, or upper chest. This is called "flushing," and it usually improves after you have been taking niacinamide on a regular basis for a few weeks. To help prevent flushing, do not drink alcohol or hot drinks when you take this medicine, and do not take it on an empty stomach. You should also ask your doctor about taking aspirin or an anti-inflammatory medicine (such as ibuprofen) before you use this medicine. Possible Side Effects While Using This Medicine: Call your doctor right away if you notice any of these side effects: Dark-colored urine or pale stools. Fast, uneven, or pounding heartbeat. Nausea, vomiting, loss of appetite, pain in your upper stomach. Yellowing of your skin or the whites of your eyes. If you notice these less serious side effects, talk with your doctor: Headache. Lightheadedness or fainting. Mild diarrhea, vomiting, or upset stomach. Muscle pain, tenderness, or weakness. Vision changes. If you notice other side effects that you think are caused by this medicine, tell your doctor. B) Niacinamide (On the skin) Niacinamide Reduces dryness, redness, or irritation of your skin caused by acne or acne medicines. When This Medicine Should Not Be Used: You should not use this medicine if you have had an allergic reaction to niacinamide. How to Use This Medicine: Cream, Gel/Jelly Your doctor will tell you how much of this medicine to use and how often. Do not use more medicine or use it more often than your doctor tells you to. This medicine is for use on the skin only. Do not get it in your eyes, nose, or mouth. Do not use it on skin areas that have cuts or scrapes. If it does get on these areas, rinse it off right away. Wash your hands with soap and water before and after using this medicine. Before using this medicine, wash your face with a mild soap or a cleansing lotion as directed by your doctor. Apply a thin layer to the affected area. Rub it in gently. You may apply cosmetics or other acne medicines over this medicine if desired. This medicine does not treat acne. Keep using all other acne medicines as directed by your doctor. If a Dose is Missed: If you miss a dose or forget to use your medicine, apply it as soon as you can. If it is almost time for your next dose, wait until then to apply the medicine and skip the missed dose. Do not apply extra medicine to make up for a missed dose. How to Store and Dispose of This Medicine: Store the medicine at room temperature, away from heat and direct light. Do not freeze. Ask your pharmacist, doctor, or health caregiver about the best way to dispose of the used medicine container and any leftover medicine after you have finished your treatment. You will also need to throw away old medicine after the expiration date has passed.Keep all medicine away from children and never share your medicine with anyone. Drugs and Foods to Avoid: Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products. Warnings While Using This Medicine: Make sure your doctor knows if you are pregnant or breast feeding. Do not use this medicine for a skin problem that has not been checked by your doctor. Your doctor will need to check your progress at regular visits while you are using this medicine. Be sure to keep all appointments. Possible Side Effects While Using This Medicine: Call your doctor right away if you notice any of these side effects: If you notice these less serious side effects, talk with your doctor: Mild skin rash. If you notice other side effects that you think are caused by this medicine, tell your doctor. Place In Therapy A) The only clear indication for niacinamide is the prevention and treatment of pellagra. Niacinamide is preferable to niacin as it produces less flushing and may be associated with a lower incidence of other adverse effects. B) Megadoses of niacinamide have no place in the treatment of schizophrenia or other psychiatric disorders. Although niacinamide may possess some degree of lipid-lowering activity, it is not indicated in the treatment of hyperlipidemia. C) Niacinamide has lessened the loss of insulin secretion in type I diabetes patients in some studies but not others. Further well-controlled trials involving larger patient populations are required to assess efficacy of the drug as a means of preserving beta-cell function in these patients. D) Although beneficial results have been observed with niacinamide therapy in some patients with bullous pemphigoid and granuloma annular, more definitive studies are needed to determine its place in therapy in these conditions. Mechanism of Action / Pharmacology A) MECHANISM OF ACTION 1) Niacinamide (nicotinamide) is the amide metabolite of niacin (nicotinic acid). Both niacinamide and niacin are water-soluble, B complex vitamins [41] [48] . 2) 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 [48] [45] [41] . 3) As B complex vitamins, niacin and niacinamide have identical physiological effects [41] . However, these vitamins differ in some of their actions. Niacin produces peripheral vasodilation and flushing, an effect not generally shared with niacinamide [41] [49] [50] [51] ; however, flushing has been observed with niacinamide in some studies [52] [49] 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 [53] [54] [50] [49] [41] . 4) 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 [45] [48] . In contrast, niacinamide has lacked this effect in most studies [55] [56] [45] , although some evidence of lipid-lowering activity has been observed with long-term administration, possibly due to conversion of niacinamide to niacin [57] [45] . 5) A deficiency of niacin results in pellagra. This condition can result from primary dietary deficiency of niacin or most commonly from secondary niacin deficiency (ie, chronic alcoholism). Either niacinamide or niacin can be used to treat pellagra [48] [41] . The amino acid tryptophan is also a dietary source of niacin, provided by animal protein. Tryptophan is converted to niacin and then niacinamide in vivo, and a deficiency of tryptophan in the diet can result in pellagra [41] [58] . Approximately 60 mg of dietary tryptophan is equivalent to 1 mg niacin [48] [41] . Tryptophan has also been used successfully in the treatment of pellagra [41] . Therapeutic Uses Carcinoma of larynx; Adjunct 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Niacinamide decreases acute hypoxia in tumors, permitting increased effectiveness of radiation treatment 3) Adult: a) Combining carbogen breathing (95% oxygen, 5% carbon dioxide) and oral nicotinamide with accelerated radiotherapy greatly increases tumor control and survival in patients with CANCER OF THE LARYNX. Because the response of cells to radiation is strongly dependent on the availability of oxygen, patients with histologically confirmed squamous cell carcinomas of the larynx at stage III or IV were given carbogen to breathe 4 minutes before and throughout radiation treatment (to increase tissue partial pressure of oxygen and thereby increase the diffusion distance of oxygen) and nicotinamide 1 hour before radiation treatment (to increase tumor perfusion). Because the probability of tumor control decreases as overall time of radiation therapy increases, treatment time was reduced by giving multiple fractions per day (accelerated radiotherapy). Sixty-two patients were given a total of 64 Gray (Gy) to the primary tumor and 68 Gy to metastatic nodes in 35 to 37 days. Doses of 2 Gy were given daily for 5 days per week until the last week and a half, when 2 doses were given twice per day, separated by 6 hours. The initial daily dose of nicotinamide was 6 grams (g), later reduced to 80 milligrams/kilogram (mg/kg), with a maximum of 6 g, because of side effects. For those experiencing severe side effects, the dose was reduced further to 60 mg/kg. Eleven patients received accelerated radiation with carbogen only and 51 received accelerated radiation with carbogen and nicotinamide. Ten patients (16%) were unable to breathe carbogen. A third of the patients receiving nicotinamide discontinued drug intake because of sideeffects (mainly nausea and vomiting). All patients developed confluent mucositis, and some required tube feeding. There was complete healing of the mucosa in all cases. At 6 weeks after treatment, there was complete regression of the primary tumor and the nodal metastases in all cases (100% response rate). This response rate is much greater than that reported with other treatments. Five patients had local recurrence at 5, 8, 14, 18, and 31 months, respectively. Of those, 2 had received carbogen only and 2 of those receiving nicotinamide had discontinued nicotinamide after 8 and 25 days, respectively. Local control rates were 92% at 2 years and 87% at 3 years. Survival was 85% at 2 years and 77% at 3 years [10] . Diabetes mellitus 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive; Pediatric, Evidence is inconclusive Recommendation: Adult, Class III; Pediatric, Class III Strength of Evidence: Adult, Category B; Pediatric, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Clinical studies have reported conflicting results regarding the efficacy of NIACINAMIDE in lessening the loss of insulin secretion in type I diabetic patients. 3) Adult: a) Controlled studies have reported that oral administration of high doses of NIACINAMIDE (3 grams daily) is effective in protecting residual beta-cell function and inducing transient remissions in type I (insulin-dependent) diabetic patients [1] [2] . In these studies, a significant reduction in INSULIN requirements and lower glycosylated hemoglobin values and improved maintenance of C-peptide responses to glucagon were observed in NIACINAMIDE treated patients as compared to controls. b) Combination therapy with oral NIACINAMIDE 50 milligrams/kilogram/day and oral CYCLOSPORINE did not significantly improve remission rates in 35 recently diagnosed type I diabetic patients in an open study [3] . Further, NIACINAMIDE administration during dose reductions of CYCLOSPORINE was unable to prevent resumption of the disease. 4) Pediatric: a) 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 [4] . 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. Granuloma annulare 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category C See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Niacinamide has been used with varying success in treating granuloma annulare. 3) Adult: a) Niacinamide 1500 milligrams/day for 6 months was successful in clearing multiple lesions in a 63-year-old woman diagnosed with granuloma annulare. Previously, topical steroids, erythromycin, and oral zinc had been ineffective. Lesions reappeared when the dose of niacinamide was reduced to 900 milligrams daily for 3 months and resolved within 2 months when the dose of 1500 milligrams was reinstituted [5] . Hyperlipidemia 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category C See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: NIACINAMIDE is not indicated for the treatment of hyperlipidemia; in contrast, NIACIN is an effective lipid-lowering agent. NIACINAMIDE may have some lipid-lowering potential in humans after long-term but not short-term use. These effects may be indirect, attributable to metabolism of NIACINAMIDE back to NIACIN. 3) Adult: a) In contrast to NIACIN, which effectively lowers serum cholesterol levels [6] , NIACINAMIDE administration in doses of 3 to 6 grams daily for up to 3 months has not resulted in lipid-lowering effects in several studies [6] [7] [8] . However, oral NIACINAMIDE in a dose of 3 grams daily for approximately 4 months was effective in reducing triglyceride levels in 1 patient with massive hypertriglyceridemia [9] . Necrobiosis lipoidica diabeticorum 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class IIb Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: In a small, open study, some patients with necrobiosis lipoidica responded to nicotinamide treatment. 3) Adult: a) Clinical improvement was reported in 8 of 13 evaluable patients with necrobiosis lipoidica following at least 1 month of oral therapy with NIACINAMIDE in an open study. Patients most likely to respond were those with pain or soreness associated with significant inflammatory change or ulceration [11] . Pellagra FDA Labeled Indication 1) Overview FDA Approval: Adult, yes; Pediatric, yes Efficacy: Adult, Effective; Pediatric, Effective Recommendation: Adult, Class I; Pediatric, Class I Strength of Evidence: Adult, Category B; Pediatric, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: NIACINAMIDE is effective in preventing NIACIN deficiency and treating PELLAGRA; it is preferred over NIACIN due to its lesser propensity to cause flushing and other adverse effects. 3) Adult: a) The daily Recommended Dietary Allowance (RDA) of NIACIN (and NIACINAMIDE) in adults is 13 to 19 milligrams. For treatment of pellagra, recommended doses in adults are 300 to 500 milligrams orally daily in divided doses [12] . 4) Pediatric: a) The daily Recommended Dietary Allowance (RDA) of niacin is 9 to 16 milligrams. b) 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 [13] . c) NIACINAMIDE 400 milligrams orally daily was effective in the treatment of a pellagralike 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 [14] . Pemphigoid 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence favors efficacy Recommendation: Adult, Class IIb Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Oral niacinamide 1 to 2.5 grams daily in combination with oral tetracycline has produced beneficial responses in some patients with BULLOUS PEMPHIGOID Adding niacinamide to tetracycline treatment for CICATRICIAL PEMPHIGOID brought clinical improvement in cases unresponsive to tetracyclines alone 3) Adult: a) Treatment of CICATRICIAL PEMPHIGOID, an autoimmune blistering disease manifested primarily in mucous membranes, with a combination of nicotinamide and tetracyclines resulted in marked clinical improvement in the 6 of 8 patients who were able to sustain full-dose treatment for 6 months. Patients had been taking tetracyclines for at least 12 weeks without adequate symptomatic control. Nicotinamide treatment was initiated at 500 milligrams (mg) daily and the dose increased by 500-mg increments at 2week intervals until symptomatic control or a dose of 3 grams per day was reached. After the maximum dose was reached, patients were maintained on that regimen for 6 months. Two patients dropped out, one after 4 weeks because of dizziness and nausea and the other after 12 weeks because of progression of disease. The other patients showed clinical improvement during treatment and at 4 months after discontinuation of treatment. None of the patients completing the study experienced adverse effects, and no liver abnormalities were detected [15] . b) Combined treatment of BULLOUS PEMPHIGOID with tetracycline, niacinamide, and a topical corticosteroid was effective in 14 of 16 patients. Initially, patients received oral oxytetracycline, 500 mg 4 times per day, oral niacinamide, 400 mg 3 times per day, and 0.5% clobetasol propionate cream once per day. Complete clearance of lesions occurred in 13 patients within 4 weeks. Another took 5 months; 2 did not respond. After clearance of lesions, the corticosteroid treatment was removed and the tetracycline was stepped down 500 mg every 4 weeks to 250 mg 4 times/day and then reduced 250 mg every 4 weeks. Then, if no new blisters appeared, niacinamide was reduced in steps of 600 mg every month. One responding patient arbitrarily discontinued treatment after 7 months and had a recurrence within 20 days that responded to the same regimen. Blood levels of osteocalcin did not change with the topical corticosteroid treatment as they do with oral administration of corticosteroids [16] . c) Niacinamide monotherapy was sufficient to control BULLOUS PEMPHIGOID in a 58year-old woman. The bullae were localized to the left breast, which had been treated with radiation and subsequent reconstruction after mastectomy. Initial treatment of the bullous pemphigoid with fluocinonide 0.05% cream was marginally successful. Subsequent treatment with tetracycline 500 milligrams (mg) twice daily and niacinamide 500 mg 3 times daily cleared lesions promptly. On 2 occasions, when her niacinamide had run out and she continued the tetracycline, new eruptions occurred in the same area, which responded immediately to resumption of niacinamide. She was then maintained on niacinamide alone, 3 times daily, without disease activity (Honl & Elston, 1998). Primary intracranial tumor; Adjunct 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Niacinamide did not increase survival time Associated with increased toxicity 3) Adult: a) High dose niacinamide (nicotinamide), given with or without carbogen (95% oxygen and 5% carbon dioxide) breathing during accelerated radiotherapy of GLIOBLASTOMA MULTIFORME, did not increase survival rate compared to carbogen alone during accelerated radiotherapy; furthermore, niacinamide treatment was associated with more frequent and more severe toxicity than was carbogen. Resistance of glioblastoma multiforme to radiation therapy is thought to result from its fast proliferative nature and to hypoxia of a large proportion of tumor cells, which makes them more aggressive and more resistant to radiotherapy. Acceleration of the radiotherapy schedule is intended to combat the fast proliferation rate; carbogen breathing and niacinamide treatment are intended to reduce the unfavorable effects of hypoxia. Niacinamide, given at 85 milligrams per kilogram per day, did not appear to be beneficial and is not a feasible treatment, owing to its toxicity [17] . Comparative Efficacy / Evaluation With Other Therapies Niacin 1) Efficacy a) As B complex vitamins, niacin and niacinamide have identical physiological effects [59] . However, these vitamins differ in other effects. Niacin produces peripheral vasodilatation and flushing, an effect not generally shared with niacinamide [59] [60] [61] [62] ; however, flushing has been observed with niacinamide in some studies [63] [60] 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 [64] [65] [61] [60] [59] . b) Niacin can also reduce serum levels of very low-density lipoprotein (VLDL) and lowdensity 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 [66] [67] . In contrast, niacinamide has lacked this effect in most studies [68] [69] [66] , although some evidence of lipid-lowering activity has been observed with long-term administration, possibly due to conversion of niacinamide to niacin [70] [66] . REFERENCES 1. Vague P, Picq R, Bernal M, et al: Effect of nicotinamide treatment on the residual insulin secretion in Type I (insulin-dependent) diabetic patients. Diabetologia 1989; 32:316-321. 2. 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