Psoriasis CNZ Gel

Clobetasol

Clobetasol is a topical, synthetic fluorinated corticosteroid. Clobetasol is used to relieve the inflammatory and pruritic manifestations of moderate to severe corticosteroid-responsive dermatoses and psoriasis. Clobetasol is one of the most potent topical corticosteroids, and is usually recommended for short-term or cyclic therapy only. Very high potency topical corticosteroids are used as an alternative to systemic therapy for localized conditions. Long-term use can lead to systemic side effects, including hypothalamic-pituitary-adrenal (HPA) axis suppression.

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. 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. 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. 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. 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. Some dosage forms are available without prescription. The FDA officially approved niacin in 1938.

Zinc Pyrithione

Zinc is a trace element. Zinc is distributed throughout the plant and animal kingdoms, second in abundance only to iron. As a trace element, zinc is essential for biologic functions and, in animals, is important in growth, appetite, testicular maturation, skin integrity, mental activity, wound healing, and immunocompetence. Zinc deficiency, first identified clinically in 1963 in young males in Iran and Egypt, is associated with diets high in unrefined cereal and unleavened bread, total parenteral nutrition (TPN), intestinal disease (i.e., Crohn’s disease, pancreatic insufficiency), alcoholism, pregnancy, or in acrodermatitis enteropathica, an autosomal recessive disease characterized by zinc malabsorption. Commercially available zinc salts include zinc acetate, zinc chloride, zinc gluconate, zinc oxide, and zinc sulfate. Zinc sulfate, administered orally or parenterally, is the most common form of zinc used when a nutritional supplement is needed; it is the salt found in zinc-containing multivitamin preparation. Zinc sulfate is also used as an ophthalmic solution for mild ocular irritation. Zinc chloride is sometimes also used for IV nutritional supplementation; oral administration of zinc chloride is associated with significant nausea. Zinc lozenges and zinc nasal spray are purported to treat symptoms of the common cold; however, in June 2009, the FDA issued a MedWatch alert advising patients and health care professionals to discontinue use of Zicam intranasal products due to more than 130 reports of loss of sense of smell (anosmia) which may be permanent or long-lasting. Zinc oxide is a mild astringent with weak antiseptic properties and is applied topically as a sun blocking agent and to treat dermatologic conditions such as abrasions, burns, chafing, diaper rash, and minor skin irritations. Additionally, the antifungal compound zinc undecylenate and the antibacterial agent bacitracin zinc contain zinc as an astringent. Zinc is also used to stabilize insulin preparations such as protamine insulin. Zinc acetate is used topically as a non-prescription agent to treat poison ivy and related Rhus dermatitis. Most recently, oral zinc acetate (Galzin) was granted FDA approval on January 29, 1997 for the oral treatment of Wilson’s disease (hepatolenticular degeneration) and is the only prescription-only zinc products.

Clobetasol

Topical corticosteroids exhibit anti-inflammatory, antipruritic, and vasoconstrictive properties. At the cellular level, corticosteroids induce peptides called lipocortins. Lipocortins antagonize phospholipase A2 , an enzyme which causes the breakdown of leukocyte lysosomal membranes to release arachidonic acid. This action decreases the subsequent formation and release of endogenous inflammatory mediators including prostaglandins, kinins, histamine, liposomal enzymes and the complement system. Early anti-inflammatory effects of topical corticosteroids include the inhibition of macrophage and leukocyte movement and activity in the inflamed area by reversing vascular dilation and permeability. Later inflammatory processes such as capillary production, collagen deposition, keloid (scar) formation also are inhibited by corticosteroids. Clinically, these actions correspond to decreased edema, erythema, pruritus, plaque formation and scaling of the affected skin.

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.

Zinc Pyrithione

Zinc is a component of many metalloenzymes in the human body. Serving as a cofactor, zinc is involved in such functions as synthesis or degradation of major metabolites (i.e., carbohydrates, lipids, proteins, nucleic acids), stabilization of protein and nucleic acid structure, transport processes, immune function, and expression of genetic information. Zinc is abundant in the nucleus of cells where it serves to stabilize RNA and DNA structure and is required for the activity of RNA polymerases important in cell division. Zinc is also present in the crystalline structure of bone, in bone enzymes, and at the zone of demarcation where it is thought to be important for adequate osteoblastic activity, formation of bone enzymes (i.e., alkaline phosphatase), and calcification.

Topically administered zinc acts as an astringent and weak antiseptic. These actions are thought to be mediated by precipitation of proteins by zinc ions. Topical zinc salts include zinc chloride, zinc stearate, zinc oxide, zinc acetate, and zinc sulfate. In addition to its astringent and antiseptic effects, zinc sulfate administered as an ophthalmic solution also aids in the clearance of mucous from the outer surface of the eye and produces mild vasodilatation, however, it does not have any decongestant activity.

Zinc deficiency is manifest in a variety of organ systems signifying the importance of the mineral for biological function and development. Clinical characterization of zinc deficiency includes growth retardation, hypogonadism and hypospermia, delayed sexual maturation, alopecia, impaired wound healing, skin lesions, immune deficiencies, behavioral disturbances, night blindness, and hypogeusia (impaired taste). Some biochemical markers of zinc deficiency include decreased plasma zinc, reduced alkaline phosphatase, low plasma testosterone, decreased retinal alcohol dehydrogenase, and decreased RNA polymerase activity in some tissues. Also, there is impaired T-lymphocyte function and decreased collagen synthesis. Zinc supplementation and adequate nutrition usually results in noticeable clinical improvement in zinc deficient patients.

Non-enzymatic proteins called metallothioneins contain large amounts of zinc. The exact role of zinc in metallothionein function is not known, however, administration of zinc stimulates the production of metallothioneins. Metallothioneins are believed to have a role in cellular antioxidant protection by scavenging free radicals. Metallothioneins bind copper with a much higher affinity than zinc, hence, the use of zinc acetate in treating Wilson’s disease and the occurrence of copper deficiency with high dose zinc therapy. In treating Wilson’s disease, zinc acetate interferes with copper absorption/reabsorption from the gut by inducing the production of metallothionein in the enterocyte, thereby preventing the serosal transfer of copper into the blood. The protein-bound copper is then excreted in the stool following desquamation of intestinal cells.

Clobetasol

Clobetasol is contraindicated in any patient with a history of corticosteroid hypersensitivity and hypersensitivity to clobetasol or any ingredients in the preparation. Although true corticosteroid hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to clobetasol should not receive any form of clobetasol. It is possible, though also rare, that such patients will display cross-hypersensitivity to other corticosteroids. It is advisable that patients who have a hypersensitivity reaction to any corticosteroid undergo skin testing, which, although not a conclusive predictor, may help to determine if hypersensitivity to another corticosteroid exists. Such patients should be carefully monitored during and following the administration of any corticosteroid.

Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) suppression and/or manifestations of Cushing’s syndrome in some patients. Clobetasol propionate has been shown to suppress the HPA axis at doses as low as 2 g/day. Conditions which increase systemic absorption include application of high-potency corticosteroids, use over large surface areas, prolonged use, use in areas where the epidermal barrier is disrupted (i.e., skin abrasion), use in pediatric patients, use in patients with hepatic disease, and the use of an occlusive dressing. Clobetasol propionate preparations should not be used with occlusive dressings. Patients receiving large doses of a potent topical corticosteroid like clobetasol should be evaluated periodically for evidence of HPA axis suppression and manifestations of Cushing’s syndrome. If these effects are noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation. Infrequently, signs and symptoms of withdrawal may occur, requiring supplemental systemic corticosteroids. It is recommended that the administration of clobetasol creams, ointments, gels, or topical solutions be limited to no more than 14 days duration, in order to limit the risk of systemic effects. Clobetasol propionate emollient creams may be administered for up to 4 weeks duration if applied to no more than 5—10% of body surface area. The total weekly dose limit of 50 g or 50 mL of a 0.05% preparation should not be exceeded for any clobetasol preparation.

Topical corticosteroids, including clobetasol, should be used with caution in patients with diabetes mellitus. Exacerbation of diabetes may occur with systemic absorption of the topical corticosteroid. Use of topical corticosteroids may further delay healing of skin ulcers in diabetic patients.

Efficacy and adverse reaction data in the pediatric population are limited for topical clobetasol; therefore use in neonates, infants, or children under 12 years of age is not recommended. Children and infants may absorb proportionally larger amounts of topical corticosteroids due to a larger skin surface area to body weight ratio, and therefore are more susceptible to developing systemic toxicity, especially with very-high-potency products. Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, growth inhibition (linear growth retardation and delayed weight gain) and increased intracranial pressure have been reported in children receiving topical corticosteroids. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Clobetasol is not approved to treat diaper dermatitis. If children are being treated in the diaper area, tight-fitting diapers or plastic pants should be avoided as these garments may act as an occlusive dressing and increase systemic absorption of the drug.

Clobetasol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Topical corticosteroids, including clobetasol, should not be used in large amounts, on large areas, or for prolonged periods of time in pregnant women. Guidelines recommend mild to moderate potency agents over potent corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birthweight has been reported with use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. There are no adequate and well-controlled studies of teratogenic effects from topical application of clobetasol in pregnant women. Corticosteroids have been shown to be teratogenic after dermal, oral, and subcutaneous administration in animal studies. Clobetasol has greater potency, and thus greater teratogenic potential, than other topical corticosteroids. After subcutaneous clobetasol propionate administration to pregnant mice and rabbits, increased malformations, such as cleft palate and skeletal abnormalities, were observed.

It is not known whether topical administration of clobetasol could result in sufficient systemic absorption to produce detectable quantities in breast milk to cause issues during breast-feeding; the manufacturers recommend to use with caution. However, most dermatologists stress that topical corticosteroids can be safely used during lactation. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. 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.

The normal inflammatory response to local infections can be masked by clobetasol. Application of topical corticosteroids to areas of infection, including tuberculosis of the skin, dermatologic fungal infection, and cutaneous or systemic viral infection (e.g., herpes infection, measles, varicella), should be initiated or continued only if the appropriate anti-infective treatment is instituted. If the infection does not respond to the antimicrobial therapy, the concurrent use of the topical corticosteroid should be discontinued until the infection is controlled. Topical corticosteroids may delay the healing of non-infected wounds, such as venous stasis ulcers. Use clobetasol preparations with caution in patients with markedly impaired circulation or peripheral vascular disease; skin ulceration has been reported in these patients following topical corticosteroid use.

As with other potent fluorinated topical corticosteroids, clobetasol should not be used to treat acne vulgaris, acne rosacea, or perioral dermatitis as clobetasol may aggravate these conditions. Clobetasol preparations should not be applied to the face, groin, vagina, or axillae. Care should be taken to avoid use around the eyes; ocular exposure should be avoided. If unintended contact happens, the patient should rinse the exposed area well with water. Visual impairment, ocular hypertension and cataracts have been reported with ocular exposure to other high potency topical corticosteroids. Preexisting glaucoma may be aggravated if clobetasol is used in the periorbital area. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

Topical corticosteroids should be used for brief periods, or under close medical supervision in patients with evidence of pre-existing skin atrophy. Geriatric patients may be more likely to have preexisting skin atrophy secondary to aging. Purpura and skin lacerations that may raise the skin and subcutaneous tissue from deep fascia may be more likely to occur with the use of topical corticosteroids in geriatric patients. Topical clobetasol clinical trials included insufficient numbers of elderly patients to do a separate analysis of efficacy and safety in this population. Based on available data, no dosage adjustments are required for elderly patients receiving topical clobetasol. Use of lower potency topical corticosteroids also may be necessary in some patients.

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. 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.

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.

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. 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. 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.

Zinc Pyrithione

Parenteral zinc salts are classified as pregnancy category C. No adequate and well-controlled trials in pregnant women have been performed with parenteral zinc. Exercise caution when using parenteral zinc supplementation during pregnancy. Adverse effects have not been reported with the normal daily intake of zinc within the recommended dietary daily intakes for a pregnant female. Galzin (oral zinc acetate) studies conducted in the US for Wilson’s disease included 19 symptomatic and presymptomatic women who became pregnant and continued treatment; these women delivered 26 live birth babies. At the time of delivery, the duration of zinc acetate therapy had ranged from 0.7 to 13.7 years and all patients were using zinc acetate within the normally recommended dosage ranges. Measurement of urinary copper excretion indicated adequate control of copper levels in most patients before and during pregnancy. The results also indicated that during pregnancy, the mothers’ health was protected by zinc acetate therapy, and no adverse effects on liver or neurological functions were reported. Limited pregnancy outcome data indicates an incidence of miscarriages consistent with those in the general population. In a separate double-blind study, 580 African-American pregnant women with low plasma zinc levels were randomized to receive daily doses of either zinc 25 mg or placebo until delivery. Higher infant birth weights and larger infant head circumferences were observed in newborns of women receiving zinc supplementation and with a body mass index (BMI) of less than 26 kg/m2.

Zinc supplementation can interfere with the absorption of copper. Administration of zinc to patients with hypocupremia (copper deficiency) can further decrease serum copper levels.

Clobetasol

Clobetasol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Topical corticosteroids, including clobetasol, should not be used in large amounts, on large areas, or for prolonged periods of time in pregnant women. Guidelines recommend mild to moderate potency agents over potent corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birthweight has been reported with use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. There are no adequate and well-controlled studies of teratogenic effects from topical application of clobetasol in pregnant women. Corticosteroids have been shown to be teratogenic after dermal, oral, and subcutaneous administration in animal studies. Clobetasol has greater potency, and thus greater teratogenic potential, than other topical corticosteroids. After subcutaneous clobetasol propionate administration to pregnant mice and rabbits, increased malformations, such as cleft palate and skeletal abnormalities, were observed.

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.

Zinc Pyrithione

Parenteral zinc salts are classified as pregnancy category C. No adequate and well-controlled trials in pregnant women have been performed with parenteral zinc. Exercise caution when using parenteral zinc supplementation during pregnancy. Adverse effects have not been reported with the normal daily intake of zinc within the recommended dietary daily intakes for a pregnant female. Galzin (oral zinc acetate) studies conducted in the US for Wilson’s disease included 19 symptomatic and presymptomatic women who became pregnant and continued treatment; these women delivered 26 live birth babies. At the time of delivery, the duration of zinc acetate therapy had ranged from 0.7 to 13.7 years and all patients were using zinc acetate within the normally recommended dosage ranges. Measurement of urinary copper excretion indicated adequate control of copper levels in most patients before and during pregnancy. The results also indicated that during pregnancy, the mothers’ health was protected by zinc acetate therapy, and no adverse effects on liver or neurological functions were reported. Limited pregnancy outcome data indicates an incidence of miscarriages consistent with those in the general population. In a separate double-blind study, 580 African-American pregnant women with low plasma zinc levels were randomized to receive daily doses of either zinc 25 mg or placebo until delivery. Higher infant birth weights and larger infant head circumferences were observed in newborns of women receiving zinc supplementation and with a body mass index (BMI) of less than 26 kg/m2.

Clobetasol

It is not known whether topical administration of clobetasol could result in sufficient systemic absorption to produce detectable quantities in breastmilk to cause issues during breastfeeding; the manufacturers recommend to use with caution. However, most dermatologists stress that topical corticosteroids can be safely used during lactation. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. 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.

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. 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. There are no safety data regarding the use of nicotinic acid in doses above the RDA during breastfeeding. 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.

Zinc Pyrithione

Maternal zinc supplementation during lactation appears to have no significant effect on zinc concentrations normally found in humanmilk. Use of zinc salts within the recommended daily dietary intake for lactating women is generally recognized as safe. Consider the benefits of breastfeeding, 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.

Clobetasol

When used for recommended treatment periods of 14 days or less, clobetasol topical preparations are usually well tolerated. The most frequently reported adverse reactions to clobetasol therapy are local in nature and include burning sensations, pruritus, and skin irritation. Burning and stinging sensations are more common with gel, emollient cream, and topical scalp foam/solution preparations of clobetasol and occur in 2—10% of patients. Other local adverse reactions reported in less than 2% of patients treated with clobetasol include acneiform rash, transient erythema, folliculitis, miliaria, perioral dermatitis, secondary infection, skin atrophy, skin hypopigmentation, skin peeling or cracking, xerosis, hypertrichosis, telangiectasia, and striae. Purpura and maculopapular rash may also occur. Additional adverse reactions related to scalp application of clobetasol include alopecia, vesicular rash, ocular irritation, and headache in roughly 0.3% of patients. Headache may be a clinical sign of elevated intracranial pressure. Adverse dermatologic effects are more likely to occur in intertriginous and facial areas, and tend to be more severe with fluorinated topical corticosteroids like clobetasol. Adverse dermatologic side effects of clobetasol are also more frequent with concurrent use of occlusive dressings. Some dermatologic effects, such as skin atrophy and striae, occur even with intermittent applications of high-potency topical corticosteroids, and may be permanent with prolonged treatment. If irritation develops, discontinue topical corticosteroids and institute appropriate therapy. The anti-inflammatory activity of topical corticosteroids may mask manifestations of infection. In the presence of dermatological infections, institute the use of an appropriate antifungal or antibacterial agent. If a favorable response does not promptly occur, discontinue the corticosteroid until the infection has been adequately controlled.

Signs and symptoms of corticosteroid withdrawal may occur with clobetasol dose reduction or discontinuation, and supplemental systemic corticosteroids may be needed. For example, disease flare may occur and HPA axis suppression may be present.

Systemic absorption of topical corticosteroids such as clobetasol can produce reversible hypothalamic-pituitary-adrenal (HPA) suppression with possible adrenocortical insufficiency after treatment discontinuation. In some patients, systemic absorption can produce manifestations of Cushing’s syndrome, hypertension, hyperglycemia, and glycosuria. Percutaneous absorption of clobetasol is dependent on many factors including the vehicle, the integrity of the epidermal barrier, duration of use, and use of an occlusive dressing. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. HPA axis suppression and increased intracranial pressure have been reported in children receiving topical corticosteroids. Manifestations of adrenocortical insufficiency in children include linear growth inhibition, delayed weight gain, low plasma cortisol concentrations, and absence of response to ACTH stimulation. Clinical signs of increased intracranial pressure include bulging fontanelles, headaches, and bilateral papilledema (i.e., pseudotumor cerebri). Clobetasol is a very-high-potency corticosteroid, and the risk of HPA axis suppression is greater than with other topical corticosteroids. However, the risk appears to be dose related. It is estimated that after 1 week of use of clobetasol at a dose of 3.5 grams twice daily (i.e., a 50-gram tube of clobetasol per week) over a 30% body surface area, 75% of adult patients will experience some degree of HPA axis suppression. In contrast, only 10% of adult patients using the equivalent of one 15-gram tube of clobetasol per week will have HPA axis suppression. One 4-week study of clobetasol emollient cream used in doses of 0.4—0.5 g twice daily in adult patients with plaque-type psoriasis resulted in no significant effects on serum cortisol concentrations or tolerability. Periodically evaluate patients applying clobetasol to a large surface area or to areas under occlusion for evidence of HPA axis suppression (using the ACTH stimulation test and urinary free cortisol test). To minimize risk of HPA axis suppression, discontinue therapy when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, reduce the frequency of application, or substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the topical corticosteroid.

Case reports describe the development of extensive visual impairment in patients secondary to the onset of glaucoma or ocular hypertension during the use of potent topical corticosteroids to treat severe atopic eczema of the face. Such adverse effects, if they occur, could lead to blindness. Cataracts have also been reported, usually with large doses or therapy greater than 6 months. The use of topical corticosteroids may also increase the risk of posterior subcapsular cataracts and retinopathy (central serous chorioretinopathy). Clobetasol is generally not recommended for application to the face. Any patient who develops changes in vision while applying clobetasol to the scalp or other areas should be evaluated for ocular hypertension. Low potency corticosteroids (e.g., hydrocortisone, dexamethasone) have been reported to be safer for short-term use around the eye area.

In general, excessive use of corticosteroids can lead to impaired wound healing. Since clobetasol is a topical corticosteroid, it should not be applied directly on or near healing wounds. A propensity for skin ulcer may develop in patients with markedly impaired circulation who use topical corticosteroids.

Tolerance may occur with the prolonged use of topical corticosteroids. Tolerance is usually described as a decreased acute vasoconstrictive response to the agent after a period of days to weeks. This may explain the dramatic responses noted initially by patients early in topical corticosteroid treatment and an apparent diminished response with time. Tolerance is reversible and may be attenuated by interrupted or cyclic schedules of application (e.g., clobetasol is given twice daily for 2—3 weeks, followed by a 1-week intermission).

Allergic contact dermatitis with corticosteroids such as clobetasol is usually diagnosed by observing a failure to heal. Appropriate diagnostic patch testing may help with the diagnosis.]

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. 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. 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. 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. 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.

Niacin interferes with glucose metabolism and can result in hyperglycemia. 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.

Niacin, especially in high doses, can cause hyperuricemia. Gout has been reported in post-marketing surveillance of Niaspan. 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.

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.

Asthenia, nervousness, insomnia, and paresthesia 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.

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

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.

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

Zinc Pyrithione

The most common adverse reactions to oral administration of zinc salts are nausea, vomiting, dyspepsia, and abdominal pain. These adverse events usually occur during high dose therapy. Adverse reactions reported with zinc acetate administration include gastric irritation and elevated pancreatic enzymes. Abdominal discomfort may be abated by administration with food.

Excessive zinc intake can lead to development of sideroblastic anemia which is characterized by anemia, leukopenia, and neutropenia. Sideroblastic anemia develops as a result of zinc-induced hypocupremia (copper deficiency). These effects are totally reversible following discontinuation of excessive zinc intake.

Store this medication 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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