Anti-Aging Vita Gel

Overview of Anti-Aging Vita Gel

Dosage Strength of Anti-Aging Vita Gel

Anti-Aging Vita Gel: (Niacinamide / Tretinoin / Vitamin C / Vitamin E) 4/0.03/5/1% 30 mL Pump

General Information

Niacinamide

Niacin (nicotinic acid or 3-pyridinecarboxylic acid) is a B-complex vitamin. Good dietary sources of niacin are animal proteins, beans, green vegetables, liver, mushrooms, peanuts, whole wheat, and unpolished rice. Niacin is also present in cereal grains but is largely bound to plant proteins, and thus is poorly absorbed after ingestion. Niacin is one of the substances used in the enrichment of refined flour, and our dietary intake of pre-formed niacin comes primarily from enriched grains. However, the body's niacin requirement is also met by the biosynthesis of niacin from tryptophan, an amino acid. For example, milk and eggs do not contain niacin, but do contain large amounts of tryptophan from which niacin is derived. Each 60 mg of excess tryptophan (after protein synthesis) is converted to approximately 1 mg of niacin. Synthesis of the vitamin from tryptophan in proteins supplies roughly half the niacin requirement in man. Iron-deficiency or inadequate pyridoxine or riboflavin status will decrease the conversion of tryptophan to niacin and may contribute to deficiency, due to an interdependence of coenzymes in the niacin production pathway. A late and serious manifestation of niacin deficiency is pellagra, a clinical symptom complex principally affecting the GI tract, skin, and CNS, producing symptoms of diarrhea, dermatitis, and dementia, respectively. Pellagra may result from a niacin- and protein-deficient diet, isoniazid therapy, or certain diseases that result in poor utilization of tryptophan. Pellagra was the only vitamin-deficiency disease to ever reach epidemic proportions in the US; pellagra is rare today in industrialized countries due to the enrichment of refined flours.

Several synonyms for niacin and niacinamide exist. Synthetic niacin could be produced by the oxidation of nicotine, and the term 'nicotinic acid' evolved. Scientists also coined the terms 'nicotinamide' and 'niacinamide' for the amide form of nicotinic acid. The term 'niacin' has been used generically since the 1940's to label foods and to avoid association of the vitamins with the nicotine alkaloid from tobacco. Thus the name 'niacin' has been used to denote both chemical forms, which are equivalent as vitamins on a weight basis. Both nicotinic acid and nicotinamide are synthesized for inclusion in nutritional supplements. However, since nicotinic acid and nicotinamide have different pharmacologic properties outside of their use as vitamins, it is important to distinguish between the two forms in pharmaceutical products.

In clinical medicine, nicotinic acid is used as an antilipemic, but nicotinamide (niacinamide) is not effective for this purpose. Nicotinic acid was the first hypolipidemic agent shown to decrease the incidence of secondary myocardial infarction (MI) and reduce total mortality in MI patients. However, no incremental benefit of coadministration of extended-release niacin with lovastatin or simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for extended-release niacin, simvastatin, or lovastatin monotherapy has been established. In addition, the AIM-HIGH trial demonstrated that the concurrent use of extended-release niacin (1500—2000 mg/day PO) and simvastatin does not result in a greater reduction in the incidence of cardiovascular events than simvastatin alone.1 These results are consistent with those of the larger HPS2-THRIVE trial in which the addition of extended-release niacin to effective statin-based therapy did not result in a greater reduction in the incidence of cardiovascular events. Furthermore, there was an increased risk of serious adverse events including an increased incidence of disturbances in diabetes control and diabetes diagnoses, as well as serious gastrointestinal, musculoskeletal, dermatological, infectious, and bleeding adverse events. There was also a statistically insignificant 9% proportional increase in the incidence of death from any cause in the niacin group.2 The ARBITER 6-HALTS trial demonstrated that the addition of extended-release niacin 2000 mg/day to statins results in significant regression in atherosclerosis as measured by carotid intima-media thickness, and is superior to the combination of ezetimibe and a statin.3 In an MRI study, the addition of extended-release niacin 2000 mg/day to statin therapy resulted in a significant reduction in carotid wall area compared to placebo.4 However, the NIA Plaque study, which was presented at the American Heart Association (AHA) 2009 Scientific Sessions, did not find a significant reduction in the progression of atherosclerosis associated with the addition of niacin to statin therapy as compared to statin monotherapy. Additionally, nicotinic acid has been used as a therapy for tinnitus, but efficacy data are scant. Some sustained-release nicotinic acid formulations have a lower incidence of flushing but a higher incidence of hepatotoxicity when compared to immediate-release forms.5 Some dosage forms are available without prescription. The FDA officially approved niacin in 1938.

Tretinoin

Tretinoin, also known as all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A. As vitamin A (retinol) derivatives, retinoids are important regulators of cell reproduction, and cell proliferation and differentiation; however, unlike vitamin A, retinoids are not converted into rhodopsin, which is needed for night vision. Topical tretinoin is indicated in the treatment of mild to moderate acne (e.g., grades I-III) and photodamaged skin. Topical tretinoin has also been used in the symptomatic management of keratinization disorders such as ichthyosis and keratosis follicularis. Tretinoin represents a new class of anticancer drugs, differentiating agents. Oral tretinoin is used in the treatment of acute promyelocytic leukemia (APL) and is undergoing phase III investigation in the treatment of Kaposi's sarcoma. In the treatment of APL, tretinoin offers a less toxic means to induce complete remission than conventional chemotherapy; however, approximately 25% of patients who receive tretinoin for the treatment of APL have experienced acute promyelocytic leukemia differentiation syndrome.6

Vitamin C

Vitamin C is a water-soluble vitamin, antioxidant, and crucial co-factor for the metabolism of carnitine and catecholamines, the production of collagen, and the absorption of dietary iron. Because vitamin C cannot be produced by humans, it must only be consumed from fruits and vegetables. Excellent sources of vitamin C include citrus fruits, berries, tomatoes, potatoes, and green leafy vegetables. Although the majority of vitamin C is entirely absorbed in the small intestine, as intraluminal concentrations rise, the percentage of absorbed vitamin C falls. Vitamin C is required for the hydroxylation of proline residues on procollagen, which results in the synthesis of mature collagen's triple helix. Skin, mucous membranes, blood vessels, and bone integrity are all jeopardized by the absence of a stable triple-helical framework. Scurvy occurs from a vitamin C deficiency as a result. The outcome is scurvy, which manifests as bleeding, hyperkeratosis, and hematological abnormalities. Scurvy is caused by a vitamin C shortage. In order for providers to direct patient therapy in the context of treatment or supplementation when it is indicated as a member of the interprofessional team, this activity describes the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, and monitoring of vitamin C.7

Vitamin E Acetate

Vitamin E is a fat-soluble vitamin found in many foods including vegetable oils, wheat germ, cereal grains, fruits, green vegetables, meat, eggs, and certain types of fish. The term 'vitamin E' actually represents a group of 8 different tocopherols, lipid-soluble compounds that are synthesized by plants and required by most animals, including humans. Of these, d-alpha-tocopherol is the naturally occurring form with the greatest vitamin activity. The synthetic form is dl-alpha-tocopherol. Commercial vitamin E preparations are formulated primarily from synthetic dl-alpha-tocopheryl acetate. This acetate ester confers stability to the compound but is less active than the natural form. Vitamin E deficiency is rare given the amounts found in normal dietary foods. Supplementation may be required in patients who suffer from malabsorptive disorders such as fat malabsorption syndrome, cystic fibrosis, chronic bowel disease (e.g., Crohn's, Celiac, and Whipple's disease), or who have undergone certain gastrointestinal surgeries (e.g., gastrectomy or gastric bypass). In children, the use of vitamin E is primarily in the form of supplementation to maintain adequate intakes to prevent deficiency.8 Pure vitamin E was first isolated from wheat germ oil in 1936, and its chemical structure was defined and synthesis achieved in 1938. The first time vitamin E was recognized by the Food and Nutrition Board of the National Research Council was in 1968. Systemic vitamin E was approved by the FDA in 1941. In addition to oral vitamin E formulations used for supplementation, several topical formulations of vitamin E are also available. Topical vitamin E formulations have been used off-label with claims of protective antioxidant effects against photoaging. The FDA has not evaluated these claims, and the ability of topical Vitamin E products to aid in the healing of minor burns and sunburns has not been substantiated.

Although early evidence had suggested the potential for vitamin E to reduce cardiovascular disease (CVD), more recent outcome studies have not shown benefits for vitamin E.910111213 The HOPE study has shown no effect of vitamin E on cardiac outcomes in high-risk patients with diabetes or vascular disease.14 The Women's Health Study (WHS), a study of approximately 40 thousand women receiving a daily dose of 400 mg (600 International Units), has shown no overall benefit for major cardiovascular events.15 The American Heart Association guidelines do not recommend vitamin E therapy for women as a preventative measure for CVD.16 As for males, results of the SU.VI.MAX study, which included a total of 13,017 subjects (including 5,141 men aged 45 to 60 years) followed for 7.5 years, has reported that supplementation with a multivitamin (containing 30 mg of vitamin E) did not reduce the incidence of ischemic CVD incidence in men.17

The results of studies addressing the off-label use of vitamin E in cancer have been inconsistent and inconclusive. Results of the HOPE-TOO trial showed that vitamin E supplementation does not prevent cancer, including prostate cancer. High-risk patients (e.g., diabetes, vascular disease) enrolled in this trial were administered a dose of 268 mg (400 International Units) daily and were followed for a median of 7 years.18 A post-interventional followup of the ATBC Study reported that the initial beneficial effects of alpha-tocopherol disappeared during postinterventional followup.19 Some studies have reported the potential benefits of vitamin E supplementation for prostate cancer. A cohort study suggested an inverse association between supplemental vitamin E use and the risk of metastatic or fatal prostate cancer among current smokers or smokers who stopped smoking.20 In the SU.VI.MAX study, vitamin E (30 mg) provided protection in men but not women, resulting in a significant reduction in total cancer incidence.17 In this trial, researchers concluded that supplementation may be effective in men due to lower baseline levels of antioxidants. A prior controlled clinical trial reported a 32% decrease in the incidence of prostate cancer among subjects receiving alpha-tocopherol compared to those not receiving alpha-tocopherol.21 The reduction was seen for clinical prostate cancer, but not for latent cancer. In this study, alpha-tocopherol and beta-carotene supplementation were given either separately or together, to 29,133 prostate cancer patients who were smokers for 5-8 years. In contrast, in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which was a long-term, multi-center, placebo-controlled trial, more than 35,000 men 50 years of age and older were randomized to receive either selenium 200 mcg and vitamin E 400 mg, selenium and placebo, vitamin E and placebo, or placebo. The trial was stopped after about 7 years when interim results found that neither drug prevented prostate cancer. Further, 2 preliminary trends of vitamin E slightly increasing the risk of prostate cancer and selenium slightly increasing the risk of diabetes were found. Follow-up data collection is ongoing.22

Mechanism of Action

Tretinoin

Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Tretinoin binds to all three RARs, but does not bind to RXRs except at very high concentrations. RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone.

Skin Disorders: By binding to RARs, tretinoin modifies gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of RARs, other mechanisms such as irritation, or both. Tretinoin appears to prevent horny cell cohesion and to increase epidermal cell turnover and mitotic activity. Subsequently, in patients with acne, expulsion of existing comedones occurs, and formation of new comedones is prevented through sloughing and expulsion of horny cells from the follicle. Tretinoin reduces the cell layers of the stratum corneum. The bacterium involved in acne, Propionibacterium acnes, and sebum production are unaffected. An additional action of tretinoin may involve keratinization inhibition, which would explain its effectiveness in treating keratinization disorders.

Photodamage: Topical tretinoin is effective in reducing fine wrinkling, mottled hyperpigmentation, roughness, and laxity associated with photodamaged skin. Ultraviolet irradiation induces three metalloproteinases in human skin: collagenase, 92-kd gelatinase, and stromelysin-1. The combined actions of these enzymes can fully degrade skin collagen. Pretreatment of skin with tretinoin inhibits the induction of these skin matrix metalloproteinase proteins and activity by 70—80% in both connective tissue and outer layers of irradiated skin.23

Acute Promyelocytic Leukemia: Similar to other retinoids, tretinoin induces cellular differentiation in malignant cells. Acute promyelocytic leukemia (APL) is caused by a genetic lesion that disrupts the alpha retinoic acid receptor (RAR-alpha) gene found on the long arm of chromosome 17 and the PML gene found on chromosome 15. The fusion protein that is formed, PML-RAR-alpha, inhibits apoptotic pathways and blocks myeloid differentiation when present in levels greater than those of the normal RAR-alpha protein. The presence of this gene translocation [t(15;17)] is used for diagnosis of APL and as a marker of response following treatment with either cytotoxic agents or tretinoin. During tretinoin treatment, cells expressing PML/RAR-alpha undergo cellular differentiation at a rate higher than normal cells. At therapeutic doses of tretinoin, the activity of the fusion protein on differentiation converts from inhibitory to stimulatory. Terminal differentiation of APL cells as the mechanism of tretinoin therapy is supported by 1) the absence of bone marrow aplasia during treatment; 2) the appearance of cells during treatment with the morphologic characteristics of maturation stages intermediate between promyelocytes and neutrophils; 3) the presence, during treatment, of PML and RAR-alpha rearrangements in peripheral blood neutrophils that disappear after treatment.24 Treatment with tretinoin reverses the bleeding diathesis seen in APL, before any morphologic response is noted. A retinoic acid syndrome, similar to capillary leak syndrome, may be seen in some patients (see Adverse Reactions). The etiology of this syndrome is unknown, but may be due to decreases in leukocyte adhesion protein activity. Resistance to tretinoin may develop due to pharmacokinetic reasons (decreased bioavailability) and/or changes in proteins involved in the cellular activity of tretinoin.

Niacinamide

Dietary requirements for niacin can be met by the ingestion of either nicotinic acid or nicotinamide; as vitamins, both have identical biochemical functions. As pharmacologic agents, however, they differ markedly. Nicotinic acid is not directly converted into nicotinamide by the body; nicotinamide is only formed as a result of coenzyme metabolism. Nicotinic acid is incorporated into a coenzyme known as nicotinamide adenine dinucleotide (NAD) in erythrocytes and other tissues. A second coenzyme, nicotinamide adenine dinucleotide phosphate (NADP), is synthesized from NAD. These two coenzymes function in at least 200 different redox reactions in cellular metabolic pathways. Nicotinamide is released from NAD by hydrolysis in the liver and intestines and is transported to other tissues; these tissues use nicotinamide to produce more NAD as needed. Together with riboflavin and other micronutrients, the NAD and NADP coenzymes work to convert fats and proteins to glucose and assist in the oxidation of glucose.

In addition to its role as a vitamin, niacin (nicotinic acid) has other dose-related pharmacologic properties. Nicotinic acid, when used for therapeutic purposes, acts on the peripheral circulation, producing dilation of cutaneous blood vessels and increasing blood flow, mainly in the face, neck, and chest. This action produces the characteristic "niacin-flush". Nicotinic acid-induced vasodilation may be related to release of histamine and/or prostacyclin. Histamine secretion can increase gastric motility and acid secretion. Flushing may result in concurrent pruritus, headaches, or pain. The flushing effects of nicotinic acid appear to be related to the 3-carboxyl radical on its pyridine ring. Nicotinamide (niacinamide), in contrast to nicotinic acid, does not contain a carboxyl radical in the 3 position on the pyridine ring and does not appear to produce flushing.

Nicotinic acid may be used as an antilipemic agent, but nicotinamide does not exhibit hypolipidemic activity. Niacin reduces total serum cholesterol, LDL, VLDL, and triglycerides, and increases HDL cholesterol. The mechanism of nicotinic acid's antilipemic effect is unknown but is unrelated to its biochemical role as a vitamin. One of nicotinic acid's primary actions is decreased hepatic synthesis of VLDL. Several mechanisms have been proposed, including inhibition of free fatty acid release from adipose tissue, increased lipoprotein lipase activity, decreased triglyceride synthesis, decreased VLDL-triglyceride transport, and an inhibition of lipolysis. This last mechanism may be due to niacin's inhibitory action on lipolytic hormones. Nicotinic acid possibly reduces LDL secondary to decreased VLDL production or enhanced hepatic clearance of LDL precursors. Nicotinic acid elevates total HDL by an unknown mechanism, but is associated with an increase in serum levels of Apo A-I and lipoprotein A-I, and a decrease in serum levels of Apo-B. Nicotinic acid is effective at elevating HDL even in patients whose only lipid abnormality is a low-HDL value. Niacin does not appear to affect the fecal excretion of fats, sterols, or bile acids. Clinical trial data suggest that women have a greater hypolipidemic response to niacin therapy than men at equivalent doses.

Vitamin C

Simple diffusion and active transport are the two mechanisms used in the energy-dependent process of absorption. Hexose transporters and sodium-dependent vitamin C transporters (SVCTs) are both implicated. The distal small intestine is the site of absorption, while renal excretion controls it. The average daily food intake of up to 100 mg is virtually entirely absorbed. The pituitary gland, the adrenal gland, the brain, leukocytes, and the eyes have the highest levels of ascorbic acid in the body.

In several reactions and metabolic processes, ascorbic acid serves as a cofactor, enzyme complement, co-substrate, and a potent antioxidant. It also improves iron absorption and stabilizes vitamin E and folic acid. It eliminates toxins and free radicals and lessens inflammatory reactions, including sepsis syndrome. 7

Contraindications/Precautions

Tretinoin

Tretinoin is contraindicated in patients who experience retinoid hypersensitivity reactions to vitamin A or other retinoids because cross-sensitivity between agents is possible. True contact allergy to tretinoin is rare.

The Atralin brand of tretinoin gel and Altreno brand of tretinoin lotion contain soluble fish proteins and should be used with caution in patients with known fish hypersensitivity. Patients should be instructed to contact their health care provider if they develop pruritus or urticaria following application.25

Approximately 25% of patients who receive tretinoin for the treatment of acute promyelocytic leukemia have experienced acute promyelocytic leukemia differentiation syndrome. When seen in association with the use of tretinoin, this syndrome is also known as retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions for more detailed description of RA-APL syndrome). Patients must be carefully monitored for any signs or symptoms of this syndrome.

In the treatment of acute promyelocytic leukemia, approximately 40% of patients will develop rapidly evolving leukocytosis, and these patients have a higher risk of life-threatening complications. High initial leukocyte counts or rapidly increasing leukocyte counts during treatment may be predictive of retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions). However, RA-APL syndrome has been observed with or without concomitant leukocytosis. The manufacturer recommends the immediate initiation of high-dose steroids if signs and symptoms of RA-APL are present together with leukocytosis. Some clinicians routinely add chemotherapy to oral tretinoin therapy when patients present with a WBC count > 5000/mm3 or in the case of a rapid increase in WBC count in leukopenic patients at the start of treatment. Consideration could be given to adding chemotherapy (usually cytarabine and an anthracycline, if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count > 5000/mm3 or immediately, for patients presenting with a WBC count of < 5000/mm3, if the WBC count reaches >= 6000/mm3 by day 5, >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28. The majority of patients do not require discontinuation of tretinoin therapy during RA-APL syndrome.

Retinoids may cause photosensitivity.26 Treatment with topical tretinoin should be postponed until sunburn has resolved to avoid exacerbation of the irritation, inflammation, and dryness associated with sunburned skin. Patients with a skin photosensitivity disorder should be closely evaluated prior to receiving tretinoin therapy. If sun exposure cannot be avoided during topical tretinoin therapy, sunscreen products and physical sun blocks (protective clothing, hats) are recommended for protection of treated areas. Sunlight (UV) exposure potentiates the inflammatory effects of tretinoin. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using topical tretinoin. Weather extremes, such as wind or cold, also may be irritating to patients receiving tretinoin.

Topical tretinoin should be avoided, if possible, in patients with eczema because severe irritation of eczematous skin is likely.

With the exception of the 0.05% lotion (approved for use in children 9 years and older) and 0.05% gel (approved for use in children 10 years and older) formulations, safety and efficacy of topical tretinoin have not been established in neonates, infants and children under 12 years of age. Children are prone to developing severe headache and pseudotumor cerebri while receiving oral tretinoin. For relief, some patients may require treatment with analgesics or lumbar puncture. The safety and efficacy of oral tretinoin in infants have not been established.25

Tretinoin cream, gel, lotion, and liquid are for external use only. Avoid ocular exposure, including eyelids, and contact with the mouth, angles of the nose, and mucous membranes. If eye contact occurs, rinse thoroughly with large amounts of water. Apply only to affected areas; accidental exposure to unaffected skin may cause irritation. Topical tretinoin is flammable; do not use near heat, open flame, or while smoking.25

Niacinamide

Patients who have a known hypersensitivity to niacin or any product component should not be given the drug.

While steady state plasma concentrations of niacin are generally higher in women than in men, the absorption, metabolism, and excretion of niacin appears to be similar in both genders. Women have been reported to have greater response to the lipid-lowering effects of nicotinic acid (niacin) when compared to men.

No overall differences in safety and efficacy were observed between geriatric and younger individuals receiving niacin. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity for some older individuals cannot be ruled out.

Niacin is contraindicated in patients who have significant or unexplained hepatic disease. Patients who consume large quantities of ethanol (alcoholism), who have risk factors for hepatic disease, or who have a past-history of gallbladder disease, jaundice, or hepatic dysfunction may receive niacin with close clinical observation. Elevations in liver function tests (LFTs) appear to be dose-related. Some sustained-release nicotinic acid (niacin) formulations have a higher incidence of hepatotoxicity when compared to immediate-release dosage forms. Extended-release nicotinic acid preparations (e.g., Niaspan, Slo-Niacin) should not be substituted for equivalent dosages of immediate-release (crystalline) niacin (e.g., Niacor and others). Follow the manufacturer-recommended initial dosage titration schedules for extended-release products, regardless of previous therapy with other niacin formulations. Monitor LFTs in all patients during therapy at roughly 6-month intervals or when clinically indicated. If transaminase levels (i.e., ALT or AST) rise to 3 times the upper limit of normal, or clinical symptoms of hepatic dysfunction are present, niacin should be discontinued.

Nicotinic acid (niacin) can stimulate histamine release, which, in turn, can stimulate gastric acid output. Niacin is contraindicated in patients with active peptic ulcer disease (PUD) because it can exacerbate PUD symptoms. Use niacin with caution in patients with a past history of peptic ulcer disease or in those on maintenance therapy to prevent PUD recurrence.

Due to its vasodilatory action, nicotinic acid (niacin) should be used with caution in those patients with uncorrected hypotension (or predisposition to orthostatic hypotension), acute myocardial infarction, or unstable angina, particularly when vasodilator medications such as nitrates, calcium channel blockers, or adrenergic blocking agents are coadministered (see Drug Interactions). Because the vasodilatory response to niacin may be more dramatic at the initiation of treatment, activities requiring mental alertness (e.g., driving or operating machinery) should not be undertaken until the response to niacin is known.

Niacin, especially in high doses, can cause hyperuricemia. Niacin should be prescribed cautiously to patients with gout (or predisposed to gout). These individuals should be advised not to purchase OTC forms of niacin without the guidance of a physician.

Niacin, especially in high doses, can cause hypophosphatemia. Although the reductions in phosphorus levels are usually transient, clinicians should monitor serum phosphorus periodically in those at risk for this electrolyte imbalance.

Rare cases of rhabdomyolysis have been reported in patients taking lipid-altering dosages of nicotinic acid (niacin) and statin-type agents concurrently (see Drug Interactions). Patients undergoing combined therapy should be carefully monitored for muscle pain, tenderness, or weakness, particularly in the early months of treatment or during periods of upward dose titration of either drug. While periodic CPK and potassium determinations may be considered, there is no evidence that these tests will prevent the occurrence of severe myopathy. If rhabdomyolysis occurs, the offending therapies should be discontinued.

Niacin, especially in high doses, may cause hyperglycemia. Niacin should be prescribed cautiously to patients with diabetes mellitus. These individuals should be advised not to purchase OTC forms of niacin without the guidance of a physician. Niacin has also been reported to cause false-positive results in urine glucose tests that contain cupric sulfate solution (e.g., Benedict's reagent, Clinitest).

Niacin therapy has been used safely in children for the treatment of nutritional niacin deficiency. However, the safety and effectiveness of nicotinic acid for the treatment of dyslipidemias have not been established in neonates, infants and children <= 16 years of age. Nicotinic acid has been used for the treatment of dyslipidemia in pediatric patients under select circumstances. Children may have an increased risk of niacin-induced side effects versus adult populations. At least one pediatric study has concluded that niacin treatment should be reserved for treatment of severe hypercholesterolemia under the close-supervision of a lipid specialist.27 In general, the National Cholesterol Education Program (NCEP) does not recommend drug therapy for the treatment of children with dyslipidemias until the age of 10 years or older.28

Since niacin is an essential nutrient, one would expect it to be safe when administered during pregnancy at doses meeting the recommended daily allowance (RDA). Niacin is categorized as pregnancy category A under these conditions. However, when used in doses greater than the RDA for dyslipidemia, or when used parenterally for the treatment of pellagra, niacin is categorized as pregnancy category C. Most manufacturers recommend against the use of niacin in dosages greater than the RDA during pregnancy. The potential benefits of high-dose niacin therapy should be weighed against risks, since toxicological studies have not been performed.1

According to a manufacturer of niacin (Niaspan), although no studies have been conducted in nursing mothers, excretion into human milk is expected. The manufacturer recommends the discontinuation of nursing or the drug due to serious adverse reactions that may occur in nursing infants from lipid-altering doses of nicotinic acid.1 Niacin, in the form of niacinamide, is excreted in breast milk in proportion to maternal intake. Niacin supplementation is only needed in those lactating women who do not have adequate dietary intake. The Recommended Daily Allowance (RDA) of the National Academy of Science for niacin during lactation is 20 mg.29 There are no safety data regarding the use of nicotinic acid in doses above the RDA during breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Use niacin with caution in patients with renal disease (renal failure or severe renal impairment) since niacin metabolites are excreted through the kidneys. It appears that no special precautions are needed when administering niacin to meet the recommended nutritional daily allowance (RDA). Use caution when administering higher dosages.

Nicotinic acid (niacin) occasionally causes slight decreases in platelet counts or increased prothrombin times and should be used with caution in patients with thrombocytopenia, coagulopathy, or who are receiving anticoagulant therapy. Patients who will be undergoing surgery should have blood counts monitored. Nicotinic acid (niacin) is contraindicated in patients with arterial bleeding.

The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, glucose and liver function tests should be evaluated regularly because niacin interferes with glucose control, can aggravate diabetes, and can exacerbate active gallbladder disease and gout. Flushing is a common side effect of niacin.30

Vitamin C

Blood conditions include thalassemia, G6PD deficiency, sickle cell disease, and hemochromatosis are contraindicated for vitamin C administration. Avoid taking supplements right before or right after having an angioplasty. Vitamin C supplements should be taken cautiously by diabetic individuals because they can boost blood sugar levels.

Because ascorbic acid acidification enhances the likelihood of the precipitation of cysteine, urate, and oxalate stones, vitamin C should be administered with caution in oxalate nephropathy or nephrolithiasis. 7

Vitamin E Acetate

The use of vitamin E supplements in high doses (more than 537 to 671 mg/day [800 to 1,000 International Units/day] PO) may increase the risk of bleeding due to vitamin K deficiency and/or anticoagulant therapy by inhibiting platelet aggregation and antagonizing vitamin K clotting factors.3132 While not specifically studied, similar effects would be expected in pediatric patients treated with high doses of vitamin E.

Vitamin E topical creams and oils are for external use only. Avoid ocular exposure, including eyelids, and contact with the mouth, angles of the nose, and mucous membranes. If eye contact occurs, rinse thoroughly with large amounts of water.

Oral supplementation of Vitamin E in amounts exceeding the RDA during pregnancy should be approached with caution. Vitamin E deficiency is rare and supplementation of vitamin E specifically during pregnancy is not necessary for females with normal fat absorption. Adverse effects have not been reported with the normal daily intake of vitamin E within the recommended dietary daily intakes for a pregnant female.8 The use of vitamin E in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved.

Vitamin E crosses the placenta and is distributed into breast milk. The amount of vitamin E that crosses the placenta appears to be less than the amount transferred to the infant via breast milk. Vitamin E concentrations in human colostrum range from 0.13 to 3.6 mg per 100 mL. The amounts in human milk range from 0.1 to 0.48 per 100 mL. Use of vitamin E within the recommended daily dietary intake for lactating women is generally recognized as safe. Oral supplementation of vitamin E during breast-feeding should be approached with caution. Vitamin E deficiency is rare, and supplementation of vitamin E specifically during lactation is not necessary for females with normal fat absorption. Topically applying vitamin E to the breasts should be avoided as it could theoretically expose the infant to additional oral vitamin E.833 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Vitamin E supplementation in premature neonates and very-low-birth-weight infants resulting in serum alpha-tocopherol concentrations more than 3.5 mg/dL has been associated with an increased risk of sepsis. In addition, serum alpha-tocopherol levels more than 3.5 mg/dL have also been associated with an increased risk of necrotizing enterocolitis in very-low-birth weight infants treated with vitamin E for more than 1 week. Serum alpha-tocopherol concentrations less than 3.5 mg/dL have not been shown to be associated with these adverse effects in premature and very-low-birth weight infants.34 It is recommended to monitor serum alpha tocopherol concentrations in these patients when vitamin E doses more than 2.7 mg/kg/day (4 International Units/kg/day) IV are administered for more than 2 weeks due to the narrow therapeutic index of vitamin E.35

Pregnancy

Tretinoin

Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. Reproductive risk should be discussed. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception requirements must be followed even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until pregnancy testing results are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.363725

Niacinamide

Since niacin is an essential nutrient, one would expect it to be safe when administered during pregnancy at doses meeting the recommended daily allowance (RDA). Niacin is categorized as pregnancy category A under these conditions. However, when used in doses greater than the RDA for dyslipidemia, or when used parenterally for the treatment of pellagra, niacin is categorized as pregnancy category C. Most manufacturers recommend against the use of niacin in dosages greater than the RDA during pregnancy. The potential benefits of high-dose niacin therapy should be weighed against risks, since toxicological studies have not been performed.1

Vitamin C

When used at doses recommended by the FDA, ascorbic acid has been classified by the FDA as pregnancy category A. Pregnancy category C has been ascribed to doses above the advised dietary intake (RDA). There haven't been any reported animal experiments. There are no controlled studies on pregnancy in humans. The use of ascorbic acid during pregnancy is only advised when the benefits outweigh the risks.

High ascorbic acid dosages taken during pregnancy have been linked to conditional scurvy in newborns.38

Vitamin E Acetate

Oral supplementation of Vitamin E in amounts exceeding the RDA during pregnancy should be approached with caution. Vitamin E deficiency is rare and supplementation of vitamin E specifically during pregnancy is not necessary for females with normal fat absorption. Adverse effects have not been reported with the normal daily intake of vitamin E within the recommended dietary daily intakes for a pregnant female.8The use of vitamin E in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved.

Breastfeeding

Tretinoin

According to the manufacturers, breastfeeding should be discontinued prior to receiving oral tretinoin and caution should be used with topical tretinoin.3637 It is unknown whether oral or topical tretinoin is distributed into breast milk. Systemic absorption of tretinoin after topical application is low 37, and therefore it is unlikely that a significant amount of the drug is excreted into breast milk. However, consideration for the use of an alternative topical agent (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin) may be appropriate for some patients. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Niacinamide

According to a manufacturer of niacin (Niaspan), although no studies have been conducted in nursing mothers, excretion into human milk is expected. The manufacturer recommends the discontinuation of nursing or the drug due to serious adverse reactions that may occur in nursing infants from lipid-altering doses of nicotinic acid.1 Niacin, in the form of niacinamide, is excreted in breast milk in proportion to maternal intake. Niacin supplementation is only needed in those lactating women who do not have adequate dietary intake. The Recommended Daily Allowance (RDA) of the National Academy of Science for niacin during lactation is 20 mg.29 There are no safety data regarding the use of nicotinic acid in doses above the RDA during breast-feeding. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Vitamin C

Human breastmilk is expelled ascorbic acid. Unknown consequences may occur in nursing infants. When giving ascorbic acid to breastfeeding mothers, the manufacturer advises using caution.38

Vitamin E Acetate

Vitamin E crosses the placenta and is distributed into breast milk. The amount of vitamin E that crosses the placenta appears to be less than the amount transferred to the infant via breast milk. Vitamin E concentrations in human colostrum range from 0.13 to 3.6 mg per 100 mL. The amounts in human milk range from 0.1 to 0.48 per 100 mL. Use of vitamin E within the recommended daily dietary intake for lactating women is generally recognized as safe. Oral supplementation of vitamin E during breastfeeding should be approached with caution. Vitamin E deficiency is rare, and supplementation of vitamin E specifically during lactation is not necessary for females with normal fat absorption. Topically applying vitamin E to the breasts should be avoided as it could theoretically expose the infant to additional oral vitamin E.833 Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Adverse Reactions/Side Effects

Tretinoin

Skin changes can occur with both topical and oral tretinoin, but are more common with topical therapy. Almost all patients report a local inflammatory response, which is reversible following discontinuance of topical treatment. Almost all patients using topical tretinoin reported skin irritation such as peeling, xerosis (dry skin), burning, stinging, erythema, and pruritus. In 32% of all study patients, severe skin irritation led to temporary discontinuation of topical tretinoin 0.02% (about 7%), or led to use of a mild topical corticosteroid. About 7% of patients using tretinoin 0.02%, compared to less than 1% of the control patients, had sufficiently severe local irritation to warrant short-term use of mild topical corticosteroids to alleviate local irritation. About 4% of patients had to discontinue use of topical tretinoin because of adverse reactions. If severe erythema, edema, vesicle formation (e.g., vesicular rash), or crusting develops, topical tretinoin should be discontinued until skin integrity is restored. Therapy may be reinitiated with less frequent application or a lower concentration. Skin hyperpigmentation and skin hypopigmentation have been reported in about 2% of patients with topical tretinoin therapy, with resolution following discontinuation of tretinoin. Some patients experience increased photosensitivity during topical or oral tretinoin therapy; patients should use sunscreen (minimum SPF 15) and protective clothing. Patients with sunburn should not use topical tretinoin until fully recovered.3940 Dry skin/mucous membranes were reported in the majority of patients (77%) receiving oral tretinoin. Other dermatologic adverse reactions reported with oral tretinoin include rash (unspecified) (54%), pruritus (20%), alopecia (14%), unspecified skin changes (14%), cellulitis (8%), facial edema (6%), and pallor (6%). Isolated cases of erythema nodosum and Sweet's syndrome have also been reported with oral tretinoin.39

Niacinamide

Niacin (nicotinic acid), when administered in doses equivalent to the RDA, is generally nontoxic. Niacinamide also rarely causes adverse reactions. Larger doses of nicotinic acid (i.e., >= 1 g/day PO), can cause adverse reactions more frequently. Differences in adverse reaction profiles can be explained by the fact that nicotinic acid has pharmacologic properties that are different from niacinamide.

Peripheral vasodilation is a well-known adverse reaction to niacin. It is characterized by flushing; warmth; and burning or tingling of the skin, especially in the face, neck, and chest. Hypotension can be caused by this vasodilation. Patients should avoid sudden changes in posture to prevent symptomatic or orthostatic hypotension. Dizziness and/or headache, including migraine, can occur. Cutaneous flushing is more likely to occur with immediate-release preparations as opposed to sustained-release ones and also increases in incidence with higher doses.5 Following 4-weeks of maintenance therapy of 1500 mg daily, patients receiving immediate-release niacin averaged 8.6 flushing events compared to 1.9 events in the Niaspan group. In placebo-controlled studies of Niaspan, flushing occurred in 55—69% of patients compared to 19% of patients receiving placebo. Flushing was described as the reason for discontinuing therapy for 6% of patients receiving Niaspan in pivotal studies.1 These reactions usually improve after the initial 2 weeks of therapy. Some patients develop generalized pruritus as a result of peripheral flushing. In placebo controlled trials, pruritus was reported in 0—8% of patients receiving Niaspan compared to 2% of patients taking placebo. Rash (unspecified) was reported in 0—5% of patients in the Niaspan group compared to no patients in the placebo group.1 Patients should avoid ethanol or hot drinks that can precipitate flushing. Flushing can be minimized by taking niacin with meals, using low initial doses, and increasing doses gradually. If necessary, taking one aspirin (e.g., 325 mg) 30 minutes before each dose can help prevent or reduce flushing. Spontaneous reports with niacin suggest that flushing may also be accompanied by symptoms of dizziness or syncope, sinus tachycardia, palpitations, atrial fibrillation, dyspnea, diaphoresis, chills, edema, or exacerbations of angina. On rare occasions, cardiac arrhythmias or syncope has occurred. Hypersensitivity or anaphylactoid reactions have been reported rarely during niacin therapy; episodes have included one or more of the following features: anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, laryngeal edema, face edema, peripheral edema, laryngospasm, maculopapular rash, and vesiculobullous rash (vesicular rash, bullous rash).

Niacin can produce a variety of GI effects, such as nausea/vomiting, abdominal pain, diarrhea, bloating, dyspepsia, or flatulence, when taken in large doses. Eructation and peptic ulcer has been reported with post-marketing experience of Niaspan. Compared to placebo, diarrhea was reported in 7—14% (vs. 13%), nausea in 4—11% (vs. 7%), and vomiting in 0—9% (vs. 4%) of patients receiving Niaspan.1 These effects are attributed to increased GI motility and may disappear after the first 2 weeks of therapy. Administering niacin with meals can reduce these adverse reactions.

Jaundice can result from chronic liver damage caused by niacin. It has been shown that elevated hepatic enzymes occur more frequently with some sustained-release niacin than with immediate-release products.5 However, in a study of 245 patients receiving Niaspan (doses ranging from 500—3000 mg/day for a mean of 17 weeks) no patients with normal serum transaminases at baseline experienced elevations to > 3x the upper limit of normal. Sustained-release products have been associated with post-marketing reports of hepatitis and jaundice, including Niaspan. Regular liver-function tests should be performed periodically. The changes in liver function induced by niacin are typically reversible with drug discontinuation. However, rare cases of fulminant hepatic necrosis and hepatic failure have been reported. Some cases have occurred after the substitution of sustained-release dosage forms for immediate-release products at directly equivalent doses; these dosage forms are not bioequivalent. Dosage titration schedules must be observed for any patient switched to a sustained-release niacin product, even if the patient was previously taking immediate-release therapy.1

Niacin interferes with glucose metabolism and can result in hyperglycemia.1 This effect is dose-related. During clinical anti-lipemic trials, increases in fasting blood glucose above normal occurred frequently (e.g., 50%) during niacin therapy. Some patients have required drug discontinuation due to hyperglycemia or exacerbation of diabetes. In the AIM-HIGH trial of patients with stable cardiovascular disease, the incidence of hyperglycemia (6.4% vs. 4.5%) and diabetes mellitus (3.6% vs. 2.2%) was higher in niacin plus simvastatin-treated patients compared to the simvastatin plus placebo group. Close blood glucose monitoring is advised for diabetic or potentially diabetic patients during treatment with niacin; adjustment of diet and/or antidiabetic therapy may be necessary.1

Niacin, especially in high doses, can cause hyperuricemia. Gout has been reported in post-marketing surveillance of Niaspan.1 Therefore, patients predisposed to gout should be treated with caution.

Niacin, especially in high doses (>= 2 g/day PO), can cause hypophosphatemia (mean decrease 13%). Serum phosphorus concentrations should be monitored periodically in patients at risk for hypophosphatemia.1

Nicotinic acid (niacin) occasionally causes slight decreases in platelet counts (mean reduction 11%) or increased prothrombin times (mean increase 4%), especially in high doses (>= 2 g/day PO). Rarely do these reactions result in coagulopathy or thrombocytopenia, but clinically significant effects might occur in patients with other risk factors or who are predisposed to these conditions.1

Asthenia, nervousness, insomnia, and paresthesias have been reported during niacin therapy. Rare cases of rhabdomyolysis have been reported in patients taking niacin (nicotinic acid) in doses >=1 g/day PO and HMG-CoA reductase inhibitors (i.e., 'statins') concurrently. In the AIM-HIGH trial, 4 cases (0.2%) of rhabdomyolysis were reported in the niacin; simvastatin group compared with 1 case in the simvastatin plus placebo group. Rhabdomyolysis may present as myopathy (myalgia, myasthenia, muscle cramps, muscle weakness, muscle tenderness, fatigue), elevations in creatinine phosphokinase (CPK), or renal dysfunction (renal tubular obstruction). Toxicity to the skeletal muscle occurs infrequently but can be a serious adverse reaction. This toxicity appears to be reversible after discontinuation of therapy.1

Niacin also has been associated with a variety of ophthalmic adverse effects including blurred vision and macular edema.1

Although uncommon, niacin may be associated with skin hyperpigmentation or acanthosis nigricans. Dry skin (xerosis) also has been reported during post-marketing surveillance of Niaspan.141

During clinical trials, increased cough was reported in <2—8% (vs. 6%) of patients receiving Niaspan compared to placebo.1

Vitamin E Acetate

Bleeding complications have been reported in adults receiving high dose vitamin E supplementation due to vitamin E inhibition of platelet aggregation and vitamin K clotting factors.3132 In very-low-birth-weight infants, the use of intravenous, high dose vitamin E supplementation has been associated with an increased risk in parenchymal cerebral hemorrhage (intracranial bleeding). Factors contributing to these toxicities in premature neonates include alpha-tocopherol serum concentrations more than 3.5 mg/dL and the composition of the injectable formulation.34

Nausea, diarrhea, and rash have been reported with the use of oral vitamin E; the oral solution, in particular, has a high osmolality that may contribute to GI intolerances such as diarrhea. Administration of the solution with food or feedings may reduce GI intolerance.42 Prolonged use of large systemic doses of vitamin E (e.g., 533 mg/day or more [800 International Units/day or more] in adults) has, in rare instances, caused breast enlargement, fatigue, intestinal cramps, weakness; blurred vision, headache, gonadal dysfunction, increased serum cholesterol and triglycerides, increased urinary estrogens and androgens, creatinuria, and decreased serum thyroxine and triiodothyronine. These effects are reversible following discontinuance of the drug.

In preterm and very low birth weight infants, vitamin E supplementation has been associated with an increased incidence of infection and/or sepsis, especially with serum alpha-tocopherol concentrations more than 3.5 mg/dL.34 High serum alpha-tocopherol concentrations are also associated with an increased risk of necrotizing enterocolitis in very-low-birth-weight infants treated with vitamin E for more than 1 week.34 Initial data reported to the FDA suggests a 30% incidence of necrotizing enterocolitis in infants with serum vitamin E concentrations more than 3.5 mg/dL compared to 4% in infants with serum alpha-tocopherol concentrations of 3.5 mg/dL or less. However, this data is limited by a low number of patients studied and disparate studies.35 Monitor serum vitamin E concentrations in these infants and also for signs and symptoms of infection or for feeding intolerance or other gastrointestinal symptoms.

Topical vitamin E products have been reported to cause contact dermatitis and other rashes; patients should report skin irritation, burning, or other unusual effects and discontinue use of the topical product if these occur.

Vitamin C

Ascorbic acid, the primary component of vitamin C, can have both beneficial and detrimental effects. Even though not all of these side effects are likely to occur, if they do, medical treatment may be required. If lower back pain with large doses occurs while taking ascorbic acid, consult a doctor as soon as possible. 43

Storage

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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