Dermatitis Atopic Cream

Tacrolimus

Tacrolimus is a calcineurin-inhibitor immunosuppressive agent that has been studied in patients receiving heart, kidney, liver, lung, pancreas, small bowel, or bone marrow transplants. Tacrolimus has been shown to be effective in graft rejection prophylaxis and in the management of acute and steroid- or cyclosporine-resistant transplant rejection, and it is considered an alternative to cyclosporine immunosuppression. Tacrolimus has been shown to be 10 to100 times more potent than cyclosporine. A review of clinical trials in liver and kidney transplantation suggests comparable patient and graft survival rates between patients receiving cyclosporine and those receiving tacrolimus, and a consistent statistically significant advantage for tacrolimus with respect to acute rejection rate. Tacrolimus has also been used for the treatment of refractory or chronic graft rejection. Tacrolimus was approved by the FDA for the prevention of liver transplant rejection in April 1994. Subsequent indications include the prophylaxis of organ rejection in patients receiving allogeneic kidney or heart transplants. An extended-release tacrolimus capsule formulation (Astagraf XL) was FDA approved for kidney transplant rejection prophylaxis in July 2013. An extended-release tablet formulation (Envarsus XR) was FDA approved for kidney transplant rejection prophylaxis in July 2015. A topical formulation of tacrolimus (Protopic) for the treatment of atopic dermatitis was FDA-approved for use in adults and children in December 2000.

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.

Tacrolimus

Tacrolimus induces immunosuppression by inhibiting the first phase of T-cell activation. The first phase of T-cell activation causes transcriptional activation of immediate and early proteins (e.g., interleukin (IL)-2, IL-3, IL-4, granulocyte-macrophage colony stimulating factor (GM-CSF), and interferon gamma) that allow T-cells to progress from the G0- to G1-phase. Tacrolimus binds to an immunophilin termed FK binding protein (FKBP), specifically FKBP12. Immunophilins (cyclophilin and FK binding proteins) are immunosuppressant-binding proteins that are distributed in all cellular compartments and play an important role in protein activation. The tacrolimus-FK binding protein complex binds to and inhibits the phosphatase activity of calcineurin. The calcineurin enzyme catalyzes critical dephosphorylation reactions necessary for early lymphokine gene transcription. Calcineurin inhibition results in blockade of signal transduction by the cytosol component of the nuclear factor of activated T-cells (NF-AT), which results in a failure to activate NF-AT regulated genes. NF-AT activated genes include those required for B-cell activation (e.g., IL-4 and CD40 ligand) and those required for T-cell activation (e.g., IL-2, TNF-alpha, and interferon gamma). Reduced circulating levels of T-cell activators result in inhibition of T-cell proliferative responses to antigens and mitogens including mixed lymphocyte reactivity and cytotoxic T-cell generation. Compared to cyclosporine, tacrolimus is about 100-times more potent in inhibiting T-cell proliferative responses.

In atopic dermatitis, topical tacrolimus acts to inhibit inflammation primarily by inhibiting T-cells. Tacrolimus may also bind to cell surface steroid receptors, inhibit the release of mast cell mediators, down-regulate IL-8 receptors, and decrease intracellular adhesion molecule-1 and E-selectin lesional blood vessel expression. These activities lead to decreased antigen recognition and down-regulation of the entire inflammatory cascade leading to a clinical response. Topical tacrolimus does not inhibit collagen synthesis and, therefore, does not cause skin atrophy as seen with corticosteroid therapy.

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.

Tacrolimus

Increased susceptibility to infection may occur with either systemic or topical use. Bacterial, viral, protozoal, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Serious viral infections reported include polyoma virus-associated nephropathy (PVAN) mostly due to BK virus infection, JC virus-associated progressive multifocal leukoencephalopathy (PML), and cytomegalovirus (CMV) infections. CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at higher risk of developing CMV viremia and CMV disease. Reactivation of a latent viral infection, especially herpes infection, can occur with immunosuppressive therapy. Monitor for infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection. Treatment with topical tacrolimus may be associated with an increased risk of varicella zoster (chickenpox or shingles) and herpes simplex infection. In the presence of these infections, the balance of risk and benefits associated with topical therapy should be evaluated. Patients should be instructed to report signs of infection promptly. Therapy requires an experienced clinician, specifically only clinicians experienced in immunosuppressant therapy and organ transplantation should use systemic tacrolimus, and the clinician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Administration of systemic tacrolimus requires a specialized care setting and should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services.

Patients receiving immunosuppressants, such as oral or injectable tacrolimus, are at increased risk for the development of lymphomas and other malignancies, particularly of the skin. Risk of developing a malignancy appears to be related to the intensity and duration of immunosuppression rather than the specific immunosuppressive agent. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients and has an association with the Epstein-Barr Virus (EBV). The risk of PTLD appears greatest in those patients who are EBV seronegative; a population that includes young children. Monitor EBV serology during tacrolimus therapy. Also, immunosuppression from the use of topical tacrolimus may influence the possible development of a new primary malignancy, especially skin cancer, lymphoma, or other lymphoproliferative disorders; rare cases of malignancy (e.g., skin and lymphoma) have been reported, but a causal relationship has not been established. Some malignant conditions such as cutaneous T-cell lymphoma may mimic atopic dermatitis; avoid the use of topical tacrolimus on premalignant and malignant skin conditions. Discontinue Protopic in the presence of acute infectious mononucleosis, and do not use Protopic in patients who are immunocompromised. Avoid continuous long-term use of topical calcineurin inhibitors such as tacrolimus ointment, and limit application to areas of involvement with atopic dermatitis. Only physicians experienced in immunosuppressant therapy and organ transplantation should use systemic tacrolimus, and the physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Patients initiating systemic tacrolimus therapy should be managed in facilities equipped and staffed with adequate laboratory and supportive medical services.

Tacrolimus ointment is not approved for use in neonates, infants, or children younger than 2 years old; only the lower concentration (tacrolimus 0.03%) ointment is recommended for use in non-immunocompromised pediatric patients aged 2 to 15 years. The long-term effect of tacrolimus on the developing immune system in infants and children is not known.5 Immediate-release capsules and granules for oral suspension are indicated for the prophylaxis of organ rejection in pediatric kidney, liver, and heart transplant patients. In general, pediatric patients require higher tacrolimus doses compared to adults; these requirements may decrease as the child grows older. If pediatric patients are converted between immediate-release formulations, perform therapeutic drug monitoring and adjust the dosage as necessary to ensure adequate tacrolimus exposure is maintained. Astagraf XL is approved in pediatric patients 4 years of age and older.  The safety and efficacy of Envarsus XR have not been established in patients less than 18 years of age.

Rare cases of acute renal failure have been reported in patients who received topical tacrolimus ointment; use the topical ointment cautiously in patients with renal impairment. Acute and chronic nephrotoxicity may occur with systemic tacrolimus therapy, especially at high doses. Monitor renal function and consider dosage reduction in patients with elevated serum creatinine (SCr) and tacrolimus whole blood concentrations greater than the recommended range. In kidney transplant recipients, treatment initiation may need to be delayed until there is evidence of renal function recovery. In liver and heart transplant recipients, consider starting at the lower end of the dosing range in patients who have pre-existing renal disease. In patients who develop renal failure while receiving tacrolimus, echocardiographic evaluation should be considered. Monitor patients with renal impairment closely; the tacrolimus dosage may need to be reduced in these patients. Consider switching to a different immunosuppressant therapy in patients who experience persistent SCr elevations despite a tacrolimus dose reduction. Acute nephrotoxicity is usually reversible and may be related to afferent renal arteriole vasoconstriction; signs and symptoms include increased SCr concentrations and oliguria. Chronic nephrotoxicity is often progressive; signs and symptoms include increased SCr concentrations, decreased graft function life, and histologic changes on renal biopsy. The risk of nephrotoxicity is increased with concomitant administration of CYP3A inhibitors (which increase tacrolimus concentrations) and drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, and protease inhibitors); do not administer tacrolimus concomitantly with cyclosporine.

Tacrolimus may cause QT prolongation and torsade de pointes; avoid use in patients with congenital long QT syndrome. Use systemic tacrolimus cautiously in patients with pre-existing cardiomyopathy or other cardiac disease associated with left ventricular dysfunction (e.g., heart failure); tacrolimus-induced myocardial hypertrophy has been reported. Consider obtaining electrocardiograms and monitoring electrolytes (i.e., magnesium, potassium, calcium) periodically during treatment for patients with congestive heart failure or bradyarrhythmias such as bradycardia. Further, use tacrolimus with caution in patients with other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

Tacrolimus may cause a variety of neurotoxicities including seizures. Symptoms may be associated with tacrolimus blood trough concentrations at or above the recommended range. Monitor concentrations closely in patients with a seizure disorder, especially in patients with concurrent renal or hepatic dysfunction. Consider dosage reduction or discontinuation if neurotoxicity occurs.

Insulin-dependent post-transplant diabetes mellitus has been reported in tacrolimus-treated renal transplant patients. Black patients and Hispanic patients post-renal transplant were at an increased risk of development of post-transplant diabetes mellitus. The risk of development of post-transplant diabetes mellitus increased with increasing whole blood trough concentrations of tacrolimus and increasing doses of corticosteroids. Patients with pre-existing hyperglycemia may require alterations in hypoglycemic therapy. Also, Black kidney transplant patients may need a higher tacrolimus dose to attain comparable trough concentrations as compared with Caucasian patients. A formal study to evaluate the pharmacokinetic disposition of tacrolimus in Black transplant patients has not been conducted, but some data are available. For example, 30 days after renal transplantation, a tacrolimus dose of 0.17 mg/kg in Caucasians led to a trough of 12.8 ng/mL. In contrast, a trough of 12.9 ng/mL was obtained with a tacrolimus dose of 0.26 mg/kg in Black patients.

Tacrolimus is contraindicated for use by patients with a hypersensitivity to tacrolimus. The intravenous formulation of tacrolimus contains polyoxyl 60 hydrogenated castor oil and is contraindicated for use by patients with polyoxyethylated castor oil hypersensitivity because anaphylaxis can occur during intravenous administration of tacrolimus. Intravenous use is recommended only for those who cannot tolerate an oral formulation, and conversion is recommended as soon as oral therapy can be tolerated to minimize the risk of anaphylactic reactions. Constantly observe patients for at least the first 30 minutes after the start of the infusion and at frequent intervals thereafter. If signs and symptoms of anaphylaxis occur, stop the infusion immediately. Epinephrine and a source of oxygen should be immediately available.

Counsel female and male patients of reproductive potential about the reproductive risk associated with tacrolimus and discuss family planning options including appropriate contraception prior to treatment initiation. Tacrolimus can cause fetal harm when administered to pregnant women. Based on animal data, infertility may occur in male and female patients receiving tacrolimus. Encourage female transplant patients who become pregnant and male patients who have fathered a pregnancy to enroll in the voluntary Transplantation Pregnancy Registry International at 1-877-955-6877 or www.transplantpregnancyregistry.org.

Patients should minimize or avoid phototherapy or sunlight (UV) exposure (natural or artificial) during tacrolimus therapy. Patients receiving immunosuppressants are at increased risk of developing lymphomas or other malignancies, especially of the skin. Inform patients of the increased risk of cancer; advise them to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using sunscreen with a high protection factor. Despite the absence of observed phototoxicity in humans, tacrolimus ointment shortened the time to skin tumor formation in an animal photocarcinogenicity study.

Tacrolimus ointment is for dermatologic use only. Avoid ocular exposure of tacrolimus ointment. Avoid use of any occlusive dressing. The safety of tacrolimus ointment has not been established with occlusive dressings, which may increase the systemic absorption of tacrolimus.

The safety of tacrolimus ointment has not been established for patients with generalized erythroderma, a widespread reddening of the skin often associated with exfoliative dermatitis. The use of tacrolimus ointment in those with ichthyosis, specifically Netherton’s syndrome (congenital ichthyosiform erythroderma), is not recommended due to the potential for increased systemic absorption of tacrolimus.

Pure red cell aplasia (PRCA) has been reported with tacrolimus therapy. Risk factors for PRCA include parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. Consider discontinuation of tacrolimus in patients diagnosed with PRCA.

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.

Tacrolimus

Tacrolimus can cause fetal harm when administered during pregnancy. Human data suggest that infants exposed to tacrolimus in utero are at risk of prematurity, birth defects/congenital anomalies, low birth weight, and fetal distress. Advise pregnant women of the potential risk to the fetus. The Transplantation Pregnancy Registry International (TPRI) is a voluntary pregnancy exposure registry that monitors outcomes of pregnancy in female transplant recipients and those fathered by male transplant recipients exposed to immunosuppressants; patients can register by contacting 1-877-955-6877 or www.transplantregistry.org. Tacrolimus may increase hyperglycemia in pregnant women with diabetes, including those with gestational diabetes. In addition, exacerbation of hypertension may increase the risk of pre-eclampsia. Monitor blood glucose concentrations and blood pressure regularly and treat as appropriate. Renal dysfunction, transient neonatal hyperkalemia, and low birth weight have been reported at the time of delivery in newborns of mothers taking tacrolimus. The experience with topical tacrolimus in pregnant women is too limited to permit assessment of the safety of its use during pregnancy. Tacrolimus should be used during pregnancy only when clearly needed.

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.

Tacrolimus

Use tacrolimus with caution during breastfeeding. Controlled lactation studies have not been conducted in humans; however, tacrolimus has been reported to be present in human milk after systemic use. The effects of tacrolimus on the breastfed infant or milk production have not been assessed. Limited data indicate that the amount of tacrolimus excreted into breast milk after systemic administration is low. In addition, no adverse reactions have been reported in nursing infants. The systemic absorption of tacrolimus after topical administration is minimal; 90% (1,253/1,391) of subjects in a pharmacokinetic trial with periodic blood sampling had blood concentrations of less than 2 ng/mL. Therefore, it is unlikely that a clinically significant exposure would occur via breast milk. Do not allow direct contact of the infant’s skin to treated areas and do not apply to the nipple area if nursing. Consider the benefits of breastfeeding, the risk of 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. 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 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.

Tacrolimus

Clinical trials of both systemic and topical tacrolimus administration have reported neurologic adverse reactions. Reactions reported with both systemic (among liver, kidney, and heart transplant recipients, unless otherwise specified) and topical administration include: abnormal thinking (3.1% to 14.9% systemic; 0.2% to less than 1% topical); anxiety, depression (less than 15%; 0% to 2%); dizziness (19% or less kidney, liver; 0.2% to less than 1%); and headache (9% to 64% adult kidney, liver; 13.9% pediatric kidney; 9% to 20%). Seizures or convulsions were also reported in all populations (less than 15% systemic; postmarketing with topical use); status epilepticus was reported postmarketing with systemic use. Agitation, confusion, hallucinations (less than 15%); mood alteration (less than 15% kidney); amnesia, elevated mood, emotional lability, encephalopathy, hemorrhage stroke, inconsolable crying, nervousness, neuralgia, psychomotor impairment, psychosis, and somnolence or drowsiness (3.1% to 14.9%) were reported with systemic administration. Migraine (0.2% to less than 1%) was reported with topical administration. Sleep-related problems include insomnia (24% to 64% kidney, liver; 1% to 4% topical), abnormal dreams (3.1% to 14.9% systemic), and nightmares (less than 15% kidney). Postmarketing, coma, delirium, cerebral infarction, hemiparesis, mental disorder, mental status changes, and posterior reversible encephalopathy syndrome (PRES) were reported with systemic use.

Adverse reactions affecting the nervous system were reported during clinical trials with tacrolimus. Reactions reported with both systemic (among liver, kidney, and heart transplant recipients, unless otherwise specified) and topical administration include syncope (3.1% to 14.9% systemic; 0.2% to less than 1% topical) and paresthesias (40% or less kidney, liver; 0% to 3% topical). Flaccid paralysis, impaired writing, incoordination, monoparesis, myoclonia, nerve compression, neuropathic pain, and quadriplegia (3.1% to 14.9%) were reported with systemic administration. Tremor (15% to 56%) was reported in kidney and liver transplant recipients. Peripheral neuropathy and hypoesthesia were reported after kidney transplant (less than 15%). Hyperesthesia (0% to 7%) and hypotonia (0.2% to less than 1%) were reported with topical use. Postmarketing, Calcineurin-Inhibitor Induced Pain Syndrome (CIPS), carpal tunnel syndrome, and dysarthria were reported with systemic tacrolimus administration.

Abnormal vision was reported during tacrolimus clinical trials, with both systemic (3.1% to 14.9% in kidney, liver, or heart transplant recipients) and topical (0.2% to less than 1%) administration. Blurred vision (less than 15%) and amblyopia (3.1% to 14.9%) were reported with systemic tacrolimus after kidney, liver, or heart transplant. Blepharitis, cataracts, conjunctival swelling, ocular pain, and xerophthalmia were reported in 0.2% to less than 1% of those who used topical tacrolimus. There were postmarketing reports of blindness, cortical blindness, optic neuropathy, optic atrophy, photophobia, aphasia, mutism, and unspecified speech disorder with systemic tacrolimus use.

During clinical trials with tacrolimus, administered both systemically (after kidney, liver, or heart transplant) and topically, adverse reactions affecting the ear were reported. Otalgia (3.1% to 14.9% systemic; 0% to 1% topical) and vertigo (3.1% to 14.9% systemic; 0.2% to less than 1% topical) were reported regardless of administration route. Tinnitus was reported in less than 15% of those receiving systemic tacrolimus. Ear disorder (unspecified) was reported with topical administration at a rate of 0.2% to less than 1%. There were postmarketing reports of hearing loss including deafness with systemic administration.

Tacrolimus can cause neurotoxicity, particularly with systemic use of high doses. Tacrolimus-induced neurotoxicity may manifest in a wide range of symptoms, from tremor and headache, insomnia, paresthesias, or dizziness, to more severe symptoms including seizures, coma, and delirium. Neurotoxicity appears more commonly in patients with elevated tacrolimus concentrations or hepatic dysfunction leading to impaired metabolism. Seizures have occurred in both adult and pediatric patients. A genetic predisposition has been suggested via ABCB1 gene mutation which may cause an alteration of P-glycoprotein function, decreasing its ability to restrict distribution of tacrolimus into the brain.

Leukoencephalopathy has been reported in adult and pediatric patients receiving tacrolimus, including reports of both progressive multifocal leukoencephalopathy (PML) and posterior reversible encephalopathy syndrome. JC virus-associated PML is an opportunistic viral brain infection. PML usually leads to severe disability or death. Consider PML, decreasing tacrolimus dosage or discontinuing tacrolimus, and consulting a neurologist in any patient with new onset neurological findings (cognitive, speaking, or visual problems; personality changes; muscle weakness). Recommendations for PML diagnosis are gadolinium-enhanced brain MRI and cerebrospinal fluid analysis for JC viral DNA. There are no predictive factors for PML and PML has no treatment, prevention, or cure. Symptoms of posterior reversible encephalopathy syndrome may include headache, altered mental status, seizures, visual disturbances, and elevated blood pressure; the diagnosis may be confirmed by radiological procedure. Maintain blood pressure control and immediately reduce tacrolimus dosage if posterior reversible encephalopathy syndrome is suspected or diagnosed. Symptoms of posterior reversible encephalopathy syndrome can be reversed by reducing tacrolimus dosage or withdrawing therapy.

Tacrolimus was administered systemically to kidney, liver, and heart transplant recipients and topically for atopic dermatitis during clinical trials. There were reports of chest pain (unspecified) (19% in kidney transplant recipients; 0.2% to 0.9% topical) and peripheral vasodilation (3.1% to 14.9% systemic; 0.2% to 0.9% topical) with both systemic and topical administration. Pericardial effusion was observed in 15% of heart transplant recipients. Flushing and deep venous thrombosis were reported in less than 15% of kidney transplant recipients. Cardiac valvulopathy was reported with topical administration (0.2% to 0.9%). Among all transplant recipients, angina pectoris, heart failure, congestive heart failure, cardiopulmonary failure, cardiovascular disorder (unspecified), phlebitis, deep thrombophlebitis, hypotension, peripheral vascular disorder, orthostatic hypotension, and thrombosis were reported at a rate of 3.1% to 14.9%. Myocardial infarction, myocardial ischemia, and cardiac arrest were reported postmarketing with systemic administration.

Rare cases of myocardial hypertrophy (i.e., cardiomyopathy), associated with clinically manifested ventricular dysfunction, have been reported in infants, children, and adults receiving systemic tacrolimus treatment. Myocardial hypertrophy appears to be reversible in most cases following dose reduction or drug discontinuation. The usual manifestation is concentric increases in the left ventricular posterior wall and interventricular septum thickness. Consider echocardiographic evaluation if renal failure or clinical manifestations of ventricular dysfunction develop. Of 20 infants, children, and adults who had evidence of myocardial hypertrophy and pre- and post-treatment echocardiograms, mean tacrolimus whole blood concentrations in the period prior to diagnosis ranged from 11 to 53 ng/mL in infants, 4 to 46 ng/mL in children, and 11 to 24 ng/mL in adults. Decrease the tacrolimus dose or discontinue treatment if myocardial hypertrophy is diagnosed.

Gastrointestinal adverse reactions have been reported with both systemic and topical tacrolimus use. GI reactions reported during clinical trials with both systemic (among liver, kidney, and heart transplant recipients, unless otherwise specified) and topical administration include: abdominal pain (59% or less systemic, kidney, liver; 1% to 3% topical); anorexia (34% or less kidney, liver; 0.2% to 0.9%); constipation (23% to 40% kidney, liver; 0.2% to 0.9%); diarrhea (25% to 72% kidney, liver; 3% to 5%); dyspepsia (28% or less kidney; 0% to 4%); gastritis, aphthous stomatitis or mouth ulceration (15% or less; 0.2% to 0.9%); gastroenteritis (7% kidney; 0% to 3%); GI disorder (unspecified), hernia, rectal disorder (unspecified) (3.1% to 14.9%; 0.2% to 0.9%); nausea (32% to 46% kidney, liver; 1% to 3%); and vomiting (14% to 29% kidney, liver; 1% to 6%). Colitis was reported in 0.2% to 0.9% of those who used tacrolimus ointment and postmarketing with systemic administration. Systemic administration in kidney, liver, or heart transplant recipients reported the following: abdominal distension, esophagitis, flatulence, and gastroesophageal reflux disease in 15% or less; and dysphagia, GI perforation, peritonitis, GI bleeding, ileus, duodenitis, gastroesophagitis, appetite stimulation, and esophageal ulceration in 3.1% to 14.9%. In pediatric transplant recipients, diarrhea (13.9% to 54%), vomiting (15%), GI bleeding (11%), and gastroenteritis (12%) were reported. Use of tacrolimus ointment 0.1% or 0.03% in either pediatric patients or adults included reports of tooth disorder (unspecified, 0% to 1%), tooth caries (0.2% to 0.9%), and dysgeusia (0.2% to 0.9%). Postmarketing reports with systemic use include impaired gastric emptying, intestinal obstruction, and stomach ulcer.

Blood-related adverse reactions have been reported with both systemic and topical tacrolimus use. Reactions reported during clinical trials with both systemic (among adult liver, kidney, and heart transplant recipients) and topical administration include anemia (5% to 65% systemic, with 65.4% of heart transplant patients having a hemoglobin less than 10 g/dL; 0.2% to 0.9% topical) and ecchymosis (3.1% to 14.9% systemic; 0.2% to 0.9% topical). In pediatric liver transplant recipients, anemia was reported in 29% of patients. Trials with systemic tacrolimus in organ transplant patients have reported coagulopathy, hypoproteinemia, increased hematocrit, abnormal hemoglobin, hypochromic anemia, polycythemia, decreased prothrombin time, and decreased iron concentrations (3.1% to 14.9%). Thrombocytopenia was reported in kidney (less than 15%), liver (14% to 24%), and heart (19%) transplant trials; among heart transplant patients, 19% had a platelet count less than 75,000 cells/mcL. Leukopenia was reported in kidney (13% to 16%) and heart (48%) transplant trials; among heart transplant patients, 33.6% had WBCs less than 3,000 cells/mcL. Leukocytosis was reported in kidney (less than 15%) and liver (8% to 23%) transplant trials. Hemolytic anemia, neutropenia, and thrombotic microangiopathy were reported after kidney transplant (less than 15%). Postmarketing reports include agranulocytosis, decreased blood fibrinogen concentration, disseminated intravascular coagulation (DIC), hemolytic-uremic syndrome, pancytopenia, prolonged aPTT, thrombotic thrombocytopenic purpura (TTP), thrombocytopenic purpura, febrile neutropenia, and increased INR.

Pure red cell aplasia has been reported postmarketing among tacrolimus recipients, but all patients reported risk factors for it such as parvovirus B19 infection, underlying disease, or concomitant medications associated with pure red cell aplasia. A mechanism for tacrolimus-induced pure red cell aplasia has not been elucidated. If pure red cell aplasia is diagnosed, consider discontinuing tacrolimus.

Topical administration of tacrolimus causes local symptoms that are common during the first few days of treatment and that usually improve as the lesions heal. Symptoms include skin burning (24% to 58% reported as burning sensation, stinging, soreness) or pruritus (22% to 46%; also seen with systemic administration, 36% or less). For 90% of the skin burning events associated with the 0.1% ointment, the duration of skin irritation varies between 2 minutes and 3 hours (median 15 minutes); the duration of pruritus was 3 minutes to 10 hours (median 20 minutes). With topical administration patients have also reported: contact dermatitis (2% to 4%); folliculitis (2% to 6%); furunculosis, leukoderma, nail disorder, seborrhea, skin hypertrophy (0.2% to 0.9%); eczema, eczema herpeticum, maculopapular rash, sunburn (0% to 2%); pustular rash (2% to 5%); skin erythema (9% to 28%); skin tingling (1% to 8%); vesicular rash (1% to 4%); and xerosis (1% to 3%). Adverse reactions reported during clinical trials with both systemic (among liver, kidney, and heart transplant recipients, unless otherwise specified) and topical administration include: acne vulgaris (less than 15% systemic; 0% to 7% topical); alopecia (less than 15%; 0% to 1%); diaphoresis, photosensitivity, skin discoloration, skin ulcer (3.1% to 14.9%; 0.2% to 0.9%); exfoliative dermatitis (3.1% to 14.9%; 0% to 3%); skin disorder (unspecified) (3.1% to 14.9%; 1% to 4%); rash (24% or less kidney, liver; 2% to 5%); and urticaria (postmarket systemic; 1% to 6% topical). Trials with systemic tacrolimus in organ transplant patients have reported: dermatitis, hyperhidrosis, hypotrichosis (less than 15%); and hirsutism (3.1% to 14.9%). Postmarketing reports include application site swelling and rosacea (topical); and skin hyperpigmentation, Stevens-Johnson syndrome, and toxic epidermal necrolysis (systemic).

Adverse reactions reported during tacrolimus clinical trials with both systemic (among liver, kidney, and heart transplant recipients, unless otherwise specified) and topical administration include: accidental injury (3.1% to 14.9% systemic, kidney; 3% to 7% topical); asthenia (52% or less liver, kidney; 0% to 3%); chills, dehydration (3.1% to 14.9% kidney; 0.2% to 0.9%); edema (18% or less; 0.2% to 0.9%); fever (38% or less liver, kidney; 1% to 21%); pain (unspecified) (24% to 63% liver, kidney; 1% to 2%); and peripheral edema (7% to 36% liver, kidney; 0% to 4%). Trials with systemic tacrolimus in organ transplant patients have reported: fatigue (16%); anasarca, falls (less than 15%); incision site complication (28%); and post-procedure pain (29%). Abnormal feeling, decreased mobility, hemorrhage (unspecified), temperature or heat intolerance, and ulcer (unspecified) were reported in 3.1% to 14.9% of patients after kidney transplant. Impaired wound healing (less than 15%) was reported in heart transplant trials. In pediatric liver transplantation trials, fever was reported in 46% of patients. With topical administration patients reported: alcohol intolerance (0% to 7%); cyst (0% to 3%); exacerbation of untreated area (0% to 1%); flu-like symptoms (23% to 31%); lymphadenopathy (1% to 3%); and dry nose, malaise, and xerostomia (0.2% to 0.9%). Feeling jittery was reported postmarketing with systemic tacrolimus.

Anaphylactoid reactions have been reported with tacrolimus administered as an injection infusion and topically (0.2% to 0.9%) as an ointment. The injection is formulated with polyoxyl 60 hydrogenated castor oil and should not be used in anyone with a hypersensitivity. Of note, the administration of any medication formulated with castor oil derivatives is associated with developing anaphylaxis. Reserve use of the injection for patients who are unable to take oral formulations. When administering the injection: have epinephrine and oxygen at the bedside; continuously observe the patient for at least the first 30 minutes of the infusion and at frequent intervals thereafter; and stop the infusion if any signs or symptoms of anaphylaxis occur. Anaphylactic shock has also been reported with the injection. Facial edema (angioedema) (1% to 2%) and other unspecified allergic reactions (4% to 12%) have been reported with the ointment. Instruct patients taking any tacrolimus formulation to immediately get medical help for breathing problems, rash, or itching. Postmarketing reports of multi-organ failure have been observed; primary graft dysfunction (24%) and graft-versus-host disease (GVHD) have occurred with systemic tacrolimus use.

Respiratory adverse reactions reported during clinical trials with both systemic (among liver, kidney, and heart transplant recipients, unless otherwise specified) and topical tacrolimus include: cough (adults, 18% or less; pediatric kidney, 11.4% to 31% systemic) including productive cough (adults, 1% to 18% topical); asthma (3.1% to 14.9%; 4% to 8%); dyspnea (29% or less kidney, liver; 0.2% to 0.9%); upper respiratory tract infection (31% pediatric kidney); and lung disorder (unspecified) (3.1% to 14.9%; 0.2% to 0.9%). Trials with systemic tacrolimus in organ transplant patients have reported: emphysema, hiccups, lung function decrease, pneumothorax, respiratory disorder (unspecified), and voice alteration (3.1% to 14.9%); and acute respiratory distress syndrome (ARDS) and pulmonary edema (less than 15%). Pleural effusion (30% to 36% adults; 22% pediatric), atelectasis (5% to 28% adults), and bronchitis (11% pediatric) were reported in liver transplant trials. Epistaxis (0.2% to 0.9%) was reported with topical administration. Interstitial lung disease, lung infiltration, pulmonary hypertension, pulmonary embolism, respiratory distress, respiratory failure, and allergic rhinitis have occurred during postmarketing experience with systemic tacrolimus.

Musculoskeletal adverse reactions reported during tacrolimus clinical trials, with both systemic (among liver, kidney, and heart transplant recipients) and topical administration, include: arthralgia (25% or less systemic; 0% to 3% topical); back pain (7.1% to 30%; 1% to 2%); joint disorder (unspecified), muscle cramps (3.1% to 14.9%; 0.2% to 0.9%); and myalgia (3.1% to 14.9%; 0% to 3%). Trials with systemic administration have reported: gout, myasthenia, spasm (3.1% to 14.9%); osteopenia, osteoporosis (less than 15%); polyarthritis; and rhabdomyolysis. With topical administration arthritis, arthropathy, bone disorder, bursitis, joint disorder (unspecified), neck pain, and tendon disorder (unspecified) were reported in 0.2% to 0.9% of patients.

Hepatic adverse reactions were reported during clinical trials with tacrolimus. Hyperbilirubinemia was reported with both systemic (3.1% to 14.9% in liver, kidney, and heart transplant patients) and topical (0.2% to 0.9%) administration. Trials in liver, kidney, and heart transplant recipients receiving systemic treatment reported cholangitis, jaundice, cholestatic jaundice, hepatitis granulomatous, increased blood GGT, ALT, AST, and alkaline phosphatase concentrations, and liver damage (unspecified) (3.1% to 14.9%). Elevated hepatic enzymes (36% or less) were reported in renal and liver transplant trials. Ascites was reported in 7% to 27% of adult patients and 17% of pediatric patients after liver transplant and postmarketing after kidney transplant. Abnormal liver function, cholestasis, hepatitis (acute and chronic), and hepatotoxicity were reported in less than 15% of patients after kidney transplant. Abnormal liver function tests (37%) and bile duct disorder (12%) were reported in pediatric patients during liver transplantation trials. Postmarketing reports with systemic tacrolimus include cirrhosis, fatty liver, hepatic cytolysis, systemic hepatic failure, hepatic necrosis, and hepatic veno-occlusive disease (VOD).

There is a risk of developing carcinoma or a new primary malignancy with immunosuppression, including treatment with tacrolimus. The risk appears to be related to the intensity and duration of immunosuppression, as opposed to the use of any specific agent. Skin cancer has been reported in 0.2% to 0.9% of patients using topical tacrolimus. Kaposi’s sarcoma has been reported in less than 15% of patients treated with systemic tacrolimus. Postmarketing reports of cancer include basal cell carcinoma, squamous cell carcinoma, lymphoma, and malignant melanoma with topical administration; and hepatosplenic t-cell lymphoma, malignant melanoma, and leukemia with systemic tacrolimus. Benign neoplasms (0.2% to 0.9%) have also been reported, including benign skin (0.2% to 0.9% topical; 3.1% to 14.9% systemic) and breast (0.2% to 0.9%) neoplasms. Inform patients of the increased risk of cancer; advise them to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using sunscreen with a high protection factor.

During clinical trials with tacrolimus, dysmenorrhea (0% to 4% topical), unintended pregnancy (0.2% to 0.9% topical), and vaginitis (0.2% to 0.9% topical; 3.1% to 14.9% systemic) were reported.

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. 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 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.

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.

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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