VA Class:VT106

ATC Class:A11HA04

AHFS Class:

• Vitamin B Complex 88:08

Generic Name(s):

• Riboflavin

Riboflavin is a water-soluble, B complex vitamin.

Riboflavin Deficiency

Riboflavin is used to prevent riboflavin deficiency and to treat ariboflavinosis. Whenever possible, poor dietary habits should be corrected, and many clinicians recommend administration of multivitamin preparations containing riboflavin in patients with vitamin deficiencies since poor dietary habits often result in concurrent deficiencies. (See Multivitamins 88:28.)

Although an adequate amount of riboflavin is usually obtained from dietary sources, riboflavin deficiency may occur in patients with long-standing infections, liver disease, alcoholism, malignancy, cardiac disease, diabetes mellitus, and those taking probenecid. Increased riboflavin requirements may be associated with pregnancy and lactation or oral contraceptive use; however, riboflavin deficiency is rarely associated with these conditions. Although recommended daily dietary allowances (RDA) for riboflavin have been related to protein allowances, energy intake, and metabolic body size, there is no evidence that riboflavin requirements are increased when energy utilization is increased.

Diagnosis of riboflavin deficiency can be aided by measuring erythrocyte glutathione reductase, erythrocyte flavin, or urinary riboflavin concentrations. Although these tests are not diagnostic, a urinary riboflavin concentration of less than 19-27 mcg/g of creatinine is suggestive of deficiency.101 Corneal vascularization is another diagnostic sign. Occasionally, when a patient's diagnosis is not clear, a trial of riboflavin may be used to diagnose riboflavin deficiency.

Dietary Requirements

The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941.101 In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs).101 DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL).101

The NAS has established an EAR and RDA for riboflavin for adults based on a combination of criteria including erythrocyte glutathione reductase activity and urinary excretion of riboflavin.101 Because evidence currently available on the role of riboflavin on lens opacities is limited, the NAS did not use risk reduction as a basis for setting the EAR and RDA.101 The EAR and RDA for children and adolescents 1-18 years of age were established based on data in adults, since data in children and adolescents currently are very limited.101 An AI has been set for infants up to 6 months of age based on the observed mean riboflavin intake of infants fed principally human milk.101 An AI for infants 6-12 months of age has been set based on the AI for younger infants and data from adults.101 (For a definition of Estimated Average Intake, Recommended Dietary Allowance, Adequate Intake, and other reference values for dietary nutrient intakes, see Uses: Dietary Requirements in Folic Acid 88:08.)

The principal goal of maintaining an adequate intake of riboflavin in the US and Canada is to prevent riboflavin deficiency (ariboflavinosis).101 Data prior to 1980 indicate that riboflavin deficiency occurred in various demographic groups in industrialized and nonindustrialized countries; riboflavin deficiency usually is accompanied by other nutritional deficiencies.101 Adequate intake of riboflavin can be accomplished through consumption of foodstuffs.101 In the US, riboflavin principally is obtained from milk, bread products, and fortified cereals.101 Riboflavin loss occurs when the vitamin is exposed to light (i.e., if milk is stored in a clear container and exposed to light).101

For specific information on currently recommended AIs and RDAs of riboflavin for various life-stage and gender groups, see Dosage: Dietary and Replacement Requirements, under Dosage and Administration.

Other Uses

Riboflavin may be useful in treating microcytic anemia that occurs in patients with a familial metabolic disease associated with splenomegaly and glutathione reductase deficiency.

Because riboflavin is readily measured in urine, riboflavin (e.g., 2.5 mg) also has been mixed with various drugs as a marker to test for patient compliance with the therapeutic regimen of these drugs. Riboflavin has been used in the management of migraine headache.102 Although further study is needed, results of a placebo-controlled, randomized trial in adults with a history of migraine headache indicate that riboflavin prophylaxis (400 mg daily) can decrease the frequency and duration of attacks; maximal benefit was evident after 3 months of riboflavin prophylaxis.102 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:92.

Although riboflavin has not been shown by well-controlled trials to have any therapeutic value, the drug also has been used for the management of acne, congenital methemoglobinemia, muscle cramps, and burning feet syndrome.

Administration

Riboflavin is usually administered orally. The drug may also be given by IM injection or IV infusion as a component of multivitamin injections. A parenteral formulation containing riboflavin alone is not currently commercially available.

Dosage

Dietary and Replacement Requirements

The Adequate Intake (AI) (see Uses: Dietary Requirements) of riboflavin currently recommended by the National Academy of Sciences (NAS) for healthy infants up to 6 months of age is 0.3 mg of riboflavin (0.04 mg/kg) daily.101 For infants 6-12 months of age, the NAS currently recommends an AI of 0.4 mg of riboflavin (0.04 mg/kg) daily.101 The Recommended Dietary Allowance (RDA) of riboflavin currently recommended by NAS for healthy children 1-3, 4-8, or 9-13 years of age is 0.5, 0.6, or 0.9 mg daily, respectively.101 In established the riboflavin dietary requirement in individuals 14 years of age or older, the NAS considered the requirement to be lower in women than men, based on women's size and average energy utilization.101 The RDA of riboflavin recommended for boys 14-19 years of age is 1.3 mg daily, and the RDA for girls 14-19 years of age is 1 mg daily.101 The RDA for healthy men of all ages (19-70 years of age and those 70 years of age or older) is 1.3 mg of riboflavin daily, and the RDA for healthy women of all ages (19-70 years of age and those 70 years of age or older) is 1.1 mg daily.101 These RDAs are not expected to be sufficient to meet the needs of individuals with severe malabsorption or those undergoing hemodialysis or peritoneal dialysis.101

During pregnancy, the need for riboflavin is increased to cover increased energy utilization and growth in maternal and fetal compartments.101 The RDA of riboflavin recommended by the NAS for pregnant women is 1.4 mg of riboflavin daily.101 Riboflavin requirements in lactating women include the amount required to maintain riboflavin status and the amount required to replace the riboflavin secreted daily in human milk.101 The RDA of riboflavin recommended by NAS for lactating women is 1.6 mg of riboflavin daily.101 Riboflavin intake higher than these RDAs may be needed by women who are pregnant with more than one fetus and mothers nursing more than one infant.101

Riboflavin Deficiency (Ariboflavinosis)

For the treatment of riboflavin deficiency in adults, the usual oral dosage of riboflavin is 5-30 mg daily given in divided doses. For the treatment of riboflavin deficiency in children, the usual oral dosage of riboflavin is 3-10 mg daily. The therapeutic response to the drug in riboflavin-deficient patients may not be dramatic. After several days, the ocular and dermatologic manifestations of deficiency improve. In deficient patients with normocytic, normochromic anemia, an increase in reticulocyte count usually occurs within a few days following oral administration of 10 mg of riboflavin daily.

Other Uses

For the treatment of microcytic anemia associated with splenomegaly and glutathione reductase deficiency, an oral riboflavin dosage of 10 mg daily for 10 days has been used.

No toxic effects have been reported with the use of riboflavin.

The rate and extent of absorption of riboflavin are reportedly affected by propantheline bromide. Prior administration of propantheline bromide delayed the rate of absorption of riboflavin but increased the total amount absorbed, presumably by increasing the residence time of riboflavin at GI absorption sites.

Laboratory Test Interferences

Large doses of riboflavin result in bright yellow urine and may interfere with urinalysis based on spectrometry or color reactions. Riboflavin may produce fluorescent substances in urine and plasma that may cause false elevations in fluorometric determinations of catecholamines and urobilinogen.

Pharmacology

In humans, an exogenous source of riboflavin is required for tissue respiration. Riboflavin is converted to the coenzyme, riboflavin 5-phosphate (flavin mononucleotide [FMN]). FMN is also converted to another coenzyme, flavin adenine dinucleotide (FAD). These coenzymes act as hydrogen-carrier molecules for several enzymes (flavoproteins) involved in oxidation-reduction reactions of organic substrates and in intermediary metabolism. Flavocoenzymes are involved in the formation of some vitamins and their coenzymes, including niacin, vitamin B₆, and vitamin B₁₂.101 Riboflavin is also indirectly involved in maintaining erythrocyte integrity.

Riboflavin deficiency (ariboflavinosis) results in a clinical syndrome characterized by cheilosis, angular stomatitis, glossitis, keratitis, scrotal skin changes, ocular changes, and seborrheic dermatitis. Normocytic, normochromic anemia and neuropathy occur in severe deficiency. Clinical signs of deficiency become evident after 3-8 months of inadequate riboflavin intake. Riboflavin deficiency generally is accompanied by other nutritional deficiencies.101 Administration of riboflavin reverses these signs of deficiency.

Pharmacokinetics

Absorption

Riboflavin is readily absorbed from the upper GI tract; however, absorption of the drug involves active transport mechanisms and the extent of GI absorption is limited by the duration of contact of the drug with the specialized segment of mucosa where absorption occurs. Riboflavin 5-phosphate is rapidly and almost completely dephosphorylated in the GI lumen before absorption occurs. The extent of GI absorption of riboflavin is increased when the drug is administered with food and is decreased in patients with hepatitis, cirrhosis, biliary obstruction, or in those receiving probenecid.

Distribution

FAD and FMN are widely distributed into body tissues, including GI mucosal cells, erythrocytes, and the liver. Free riboflavin is present in the retina. Riboflavin is stored in limited amounts in the liver, spleen, kidneys, and heart, mainly in the form of FAD. In blood, about 60% of FAD and FMN is protein bound. Riboflavin crosses the placenta. Milk of nursing women receiving a normal diet contains approximately 350 ng of riboflavin per mL.101

Elimination

The biologic half-life of riboflavin is about 66-84 minutes following oral or IM administration of a single large dose in healthy individuals.

Although the exact metabolic fate of riboflavin has not been clearly established, the drug is phosphorylated to FMN in GI mucosal cells, erythrocytes, and the liver; FMN is converted to FAD in the liver.

Following ingestion of usual physiologic doses of riboflavin, only about 9% of the drug is excreted in urine unchanged. The fate of the remainder of the drug is unknown. Excretion of riboflavin appears to involve renal tubular secretion as well as glomerular filtration. As the dose of riboflavin increases, larger amounts of the drug are excreted unchanged in urine. Riboflavin is more slowly removed by hemodialysis than by normal renal excretion.

Chemistry and Stability

Chemistry

Riboflavin is a water-soluble, B complex vitamin which is present in many foods including milk, meat, eggs, nuts, enriched flour, and green vegetables. Commercially available riboflavin, riboflavin 5-phosphate, and riboflavin 5-phosphate sodium are prepared synthetically; riboflavin 5-phosphate and its sodium salt are available only as components of combination preparations. Riboflavin occurs as a yellow to orange-yellow, crystalline powder having a slight odor. The drug is very slightly soluble in water and in alcohol. Riboflavin has a pK_a of 10.2.

Stability

Riboflavin is incompatible with alkaline solutions and with tetracycline, erythromycin, and streptomycin. Solutions of riboflavin should be protected from air and light. Riboflavin tablets should be stored in tight, light-resistant containers at a temperature less than 40°C, preferably between 15-30°C.

Only references cited for selected revisions after 1984 are available electronically.

100. National Research Council Food and Nutrition Board Subcommittee on the Tenth Edition of the RDAs. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press; 1989:132-7.

101. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B₆, folate, vitamin B₁₂, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998. (Prepublication copy uncorrected proofs.)

102. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis: a randomized controlled trial. Neurology . 1998; 50:466-70. [PubMed 9484373]