Acne Keto Cream

Overview of Acne Keto Cream

Dosage Strength of Acne Keto Cream

Ketoconazole / Niacinamide 2/4% 30 mL Pump

General Information

Ketoconazole

Ketoconazole is an imidazole antifungal agent and is available as an oral tablet and various topical formulations. Oral ketoconazole has been associated with fatal hepatotoxicity, adrenal gland suppression, and harmful drug interactions. Due to the potential for severe adverse events, oral ketoconazole should only be used to treat serious blastomycosis, histomycosis, coccidioidomycosis, paracoccidioidomycosis, and chromomycosis infections when no other antifungal therapies are available. The topical formulations are indicated for the treatment of tinea corporis, tinea cruris, tinea pedis, tinea versicolor, mucocutaneous candidiasis, seborrheic dermatitis, and dandruff. Ketoconazole was FDA-approved in 1981.12345

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.6 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.7 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.8 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.9 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.10 Some dosage forms are available without prescription. The FDA officially approved niacin in 1938.

Mechanism of Action

Ketoconazole

Like other azole antifungals, ketoconazole exerts its effect by altering the fungal cell membrane. Ketoconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 enzyme that is necessary for the conversion of lanosterol to ergosterol, an essential component of the membrane. In contrast, amphotericin B binds to ergosterol after it is synthesized. Inhibition of ergosterol synthesis results in increased cellular permeability, which causes leakage of cellular contents. Ketoconazole does not appear to have the same effects on human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed11 and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of yeast transformation to mycelial forms. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis.12 At higher concentrations, ketoconazole may have a direct physiochemical effect on the fungal cell membrane, which leads to a fungicidal action.

Ketoconazole possesses actions that may make it useful in conditions other than fungal infections. Ketoconazole can inhibit sterol synthesis in humans including the synthesis of aldosterone, cortisol, and testosterone. Ketoconazole's effects on testosterone synthesis occur at lower doses than do the effects on cortisol synthesis; doses of of 200—400 mg/day can inhibit testosterone secretion and doses of 400—600 mg/day have been shown to inhibit cortisol synthesis.1314 Ketoconazole acts at many of same steps as metyrapone and, in some sites, has been shown to be a more potent inhibitor.13Both ketoconazole and metyrapone affect multiple steps in the steroid-synthesis pathway, while finasteride appears to work at a single site. Ketoconazole has been used successfully for treating advanced prostate cancer.15 Finally, ketoconazole is a known potent inhibitor of thromboxane synthesis and has been used clinically to prevent ARDS in patients at high risk of this syndrome.[24000]

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.

Pharmacokinetics

Ketoconazole

Ketoconazole is administered orally and via topical administration. It is widely distributed into most body fluids, although CNS penetration is unpredictable and usually minimal. In animal studies, it crosses the placenta and is distributed into milk. Protein binding is 84—99%, mainly to albumin.

Ketoconazole plasma concentrations decline in a biphasic manner. Initial phase half-life is approximately 2 hours, and the terminal phase half-life is approximately 8 hours. It is partially metabolized through oxidation, dealkylation, and aromatic hydroxylation. Most of the ketoconazole and its metabolites are excreted into the bile and then the feces. The rest is excreted in the urine. In a study involving fasting adults with normal renal function, about 57% of a 200 mg oral dose was excreted in the feces within 4 days. Between 20—65% of the ketoconazole excreted in the feces was unchanged drug. Within 4 days, approximately 13% of the dose was excreted in the urine; approximately 2—4% of this portion was as unchanged ketoconazole.1

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9, CYP2C19, P-gp, UGT1A1, UGT2B7

Ketoconazole is a substrate and potent inhibitor of the CYP3A4 isoenzyme. In vitro, ketoconazole weakly inhibits CYP2C9 and CYP2C19; however, the in vivo inhibition potential is questionable. Ketoconazole has the ability to inhibit P-glycoprotein (P-gp) in vitro, but the potency of this inhibition may vary depending on the in vitro model or P-gp substrate used in the assay.161 Studies have also found ketoconazole to be an inhibitor of uridine diphosphoglucuronosyltransferase UGT1A1 and UGT2B7.171819

Topical ketoconazole does not have significant systemic absorption. Repeated topical application of ketoconazole 2% shampoo, however, will lead to absorption of the drug into hair keratin. Small amounts of intravaginal ketoconazole are absorbed systemically. Peak plasma concentrations in women receiving ketoconazole as a 400 mg vaginal suppository ranged from 0—20.7 ng/mL.

Niacinamide

Nicotinic acid may be administered by the oral or parenteral routes. Nicotinamide is administered orally. Niacin is widely distributed throughout the body and it concentrates in the liver, spleen, and adipose tissue. Niacin undergoes rapid and extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. Niacin is conjugated with glycine to form nicotinuric acid (NUA), which is then excreted in the urine. Some reversible metabolism from NUA back to niacin may occur in small amounts. The other pathway results in the formation of NAD. Nicotinamide is most likely released after the formation of NAD. Nicotinamide does not have hypolipidemic activity, and is further metabolized in the liver to produce N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is metabolized to two other N-methylated compounds known as 2PY and 4PY, which are excreted in the urine. The formation of 2PY predominates over 4PY in humans. Roughly 12% of nicotinic acid is excreted unchanged in the urine with normal dosages. Greater proportions of niacin are renally excreted unchanged as dosages exceed 1000 mg/day and metabolic pathways become saturated.

Contraindications/Precautions

Ketoconazole

Due to its potent inhibition of the hepatic isoenzyme CYP3A4, oral ketoconazole coadministration with other drugs metabolized by CYP3A4 should be done with extreme caution, if at all. Ketoconazole can cause elevated plasma concentrations of selected drugs metabolized via CYP3A4 which may prolong the QT interval, sometimes resulting in life-threatening ventricular arrhythmias such as torsade de pointes; use of ketoconazole with such drugs is contraindicated. Oral ketoconazole may also inhibit the metabolism of many other drugs, which could result in serious and potentially life-threatening adverse reactions, and use with selected drugs is also contraindicated.1 Due to the potential for harmful drug interactions and other serious adverse effects, oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available.45 Systemic ketoconazole can prolong the QT interval. Use ketoconazole tablets with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, 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, older adult patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.1202122232425

Ketoconazole oral tablets may cause adrenal insufficiency at doses of 400 mg/day and higher in adults. This effect is not shared with other azole antifungals. The recommended dose of 200 to 400 mg daily in adults should not be exceeded. Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.).1 Due to the risk of adrenal insufficiency and other serious adverse effects, oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available.45

Ketoconazole should be used with caution in patients with known azole antifungals hypersensitivity. Hypersensitivity reactions may be due to the various vehicles present in the different ketoconazole formulations. Ketoconazole may have a cross sensitivity with other azole derivatives such as itraconazole, fluconazole, clotrimazole, and miconazole. In rare cases, patients receiving ketoconazole have reported hypersensitivity reactions and even anaphylaxis. Ketoconazole is contraindicated in patients who have previously demonstrated these reactions.

Avoid accidental ocular exposure of topical ketoconazole products. If ocular exposure occurs, treat by immediate flushing the affected eye with cool, clean water. Contact an ophthalmologist if eye irritation persists.

Some topical ketoconazole products are flammable. Due to the alcohol content of ketoconazole topical gel (e.g., Xolegel gel) and the alcohol, butane, and proprane content of ketoconazole topical foam (e.g., Extina foam), avoid fire, flame, or tobacco smoking during and immediately after the application of these ketoconazole products.

Dizziness or drowsiness occurs in some patients receiving systemic ketoconazole. Patients should be careful driving or operating machinery if they have these reactions.

Due to the risk of severe drug interactions and other serious adverse effects with ketoconazole oral tablets, ketoconazole oral tablets should not be a first-line treatment for any fungal infection in the geriatric patient.4 1 Systemic ketoconazole can prolong the QT interval. Geriatric patients may be at increased risk for QT prolongation and for serious drug-drug interactions that may increase the risk QT prolongation risk or may increase the risk for other serious side effects.1202122232425 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, systemic azole antifungals should be used in the lowest possible dose for the shortest possible duration, particularly in patients receiving other medications known to interact with these medications. Increased monitoring may be required to identify and minimize the toxicity of warfarin, phenytoin, theophylline, or sulfonylureas when an azole antifungal is co-administered; other medications such as rifampin and cimetidine may decrease the therapeutic effect of the antifungal. Some drug-drug combinations may be contraindicated. OBRA guidelines caution that azole antifungals may cause hepatotoxicity, headaches, and GI distress.26

The safety and efficacy of oral ketoconazole have not been established in neonates, infants, or children under 2 years of age.1 Topical products (e.g., shampoo, cream) have been used in pediatric patients off-label but are not FDA-approved for use in pediatric patients; the safety and efficacy of ketoconazole topical foam and gel products have not been established in pediatric patients less than 12 years old.2272829

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.30 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.31

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.6

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.6 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.32 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.26

Pregnancy

Ketoconazole

There are no adequate and well-controlled studies of ketoconazole use during human pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Use ketoconazole in pregnant women only if the potential benefit justifies the potential risk to the fetus.1292 Guidelines recommend against starting oral azole antifungals, including ketoconazole, during pregnancy and to discontinue these agents in HIV-positive women who become pregnant.33 Embryotoxic and teratogenic effects (syndactylia and oligodactylia) have been demonstrated in animals receiving oral ketoconazole doses at 10-times the maximum recommended human dose. In addition, dystocia was observed in animals administered oral ketoconazole during the third trimester of gestation at doses approximately one-fourth the maximum human dose, based on body surface area comparisons. Ketoconazole is not detected in human plasma after chronic shampooing of the scalp.12

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.6

Breast-feeding

Ketoconazole

Systemic ketoconazole is excreted in breast milk. In a case report of a mother prescribed 200 mg PO daily for 10 days, ketoconazole milk concentrations of 0.22 mcg/mL (peak) were observed 3.25 hours post-dose and were undetectable at 24 hours post-dose. Assuming a milk intake of 150 mL/kg/day, the daily ketoconazole dose of an exclusively breast-fed infant was calculated as 0.01 mg/kg/day or 0.4% of the mother's weight-adjusted dose. There are no data on the effects of ketoconazole on the breast-fed infant or its effects on milk production. The manufacturer recommends mothers refrain from breast-feeding their infants during oral therapy; however, previous American Academy of Pediatrics (AAP) recommendations considered ketoconazole compatible with breast-feeding. After topical application, ketoconazole concentrations in plasma are low; therefore, concentrations in human breast milk are likely to be low. Advise breast-feeding women not to apply topical ketoconazole directly to the nipple and areola to avoid direct infant exposure. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for topical ketoconazole and any potential adverse effects on the breast-fed infant from ketoconazole or the underlying maternal condition. Fluconazole may be a potential alternative to consider during breast-feeding.3412922835

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.6 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.32 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.

Adverse Reactions/Side Effects

Ketoconazole

Approximately 3% of patients receiving oral ketoconazole experience episodes of nausea and vomiting. This usually is transient and may improve when ketoconazole is given with food, which also can increase oral bioavailability. Other ketoconazole-associated gastrointestinal adverse reactions include abdominal pain and diarrhea which were reported in 1.2% and less than 1% of patients, respectively.1 Cases of cheilitis have been noted during postmarketing use of ketoconazole topical foam. Due to the voluntary nature of postmarketing reports, neither a frequency nor definitive causal relationship can be established.28

Ketoconazole can inhibit testosterone secretion at doses of 200—400 mg/day13and can inhibit cortisol synthesis in doses of 400—600 mg/day.14 Inhibition of testosterone synthesis has led to cases of gynecomastia and impotence (erectile dysfunction) in < 1% of men. Serum testosterone concentrations return to baseline and gynecomastia and impotence usually abate after ketoconazole therapy is stopped. Oligospermia has been reported in patients receiving systemic ketoconazole in investigational studies. This was mainly at doses above those approved. Oligospermia was not reported at doses up to 400 mg/day; however, sperm counts are not frequently obtained at these doses.1

Rare cases of anaphylactoid reactions have been reported following the first dose of oral ketoconazole and during post-marketing use of the 2% shampoo. Several cases of hypersensitivity reactions including urticaria and angioedema have also been reported.2 Fever and chills have been reported in < 1% of patients receiving systemic ketoconazole.1 Facial swelling has been reported in < 1% of patients using the topical gel formulation.36

Dizziness, drowsiness (somnolence), and headache have been reported in < 1% of patients receiving treatment with oral ketoconazole. Neuropsychiatric events have also been reported rarely and include suicidal ideation and severe depression.1 Headache and dizziness were also reported in < 1% of patients using the topical gel formulation.36

Photophobia occurs in < 1% of patients receiving treatment with oral ketoconazole. To minimize discomfort, the patient should wear sunglasses while outside and avoid bright light when possible.1 Treatment-related ophthalmic adverse events reported in < 1% of patients using the topical gel include ocular irritation, ocular swelling, and keratoconjunctivitis sicca.36

Post-marketing worldwide reports in patients receiving oral ketoconazole have included rare cases of paresthesias, and signs of increased intracranial pressure including bulging fontanelles and papilledema. Hypertriglyceridemia has also been reported with the oral formulation but a causal relationship with ketoconazole has not been determined.1 Paresthesias have also been reported in <= 1% of patients using the topical foam and in < 1% of patients using the topical gel.3628

Dermatologic reactions were reported with systemic and topical ketoconazole formulations. Pruritus has been reported in 1.5% of patients receiving oral ketoconazole; it has also been reported following application of the topical cream, topical foam (up to 1%), topical gel (less than 1%), and the shampoo. Alopecia has been reported with the shampoo and with worldwide postmarketing reports in patients receiving the oral formulation. Skin irritation has been reported with topical use, specifically with the cream (as pruritus, burning, and stinging), the foam (up to 1%), the gel (less than 1%), and the shampoo. Contact dermatitis was reported with use of the shampoo and postmarketing with the cream; application site dermatitis was reported with use of the gel (less than 1%). The topical foam (Extina) was associated with an increased incidence of contact sensitization, including photosensitivity in dermal safety studies. Application site reaction (6%) and burning (10%) were reported with ketoconazole foam, burning was also reported with the gel (4%) and the shampoo. Skin dryness or xerosis was reported with use of the foam (up to 1%), the gel (less than 1%), and the shampoo. Erythema was reported with use of the foam (up to 1%) and the gel (less than 1%). Rash (unspecified) was reported with use of the foam (up to 1%) and the shampoo. Warmth at the application site was noted in up to 1% of patients using the foam. Pustules were noted on the skin with application of the gel (less than 1%) and on the scalp with application of the shampoo. Other reactions noted in less than 1% of patients who used the topical gel include discharge, pain, impetigo, pyogenic granuloma, acne vulgaris, and nail discoloration. Adverse reactions specifically noted with use of the shampoo include hair discoloration, abnormal hair texture and removal of curl, rash (unspecified), and application site reactions.21272829

Systemic ketoconazole can prolong the QT interval. Serious cardiovascular events, QT prolongation, ventricular arrhythmias, and torsade de pointes, have been observed in patients receiving ketoconazole oral tablets in combination with other QT-prolonging drugs.1

Ketoconazole alters vitamin D metabolism and may lead to vitamin D deficiency. Patients should be monitored and supplemented with vitamin D if necessary.

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.10 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.6 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.6 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.6 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.10 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.6

Niacin interferes with glucose metabolism and can result in hyperglycemia.6 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.6

Niacin, especially in high doses, can cause hyperuricemia. Gout has been reported in post-marketing surveillance of Niaspan.6 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.6

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.6

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.6

Niacin also has been associated with a variety of ophthalmic adverse effects including blurred vision and macular edema.6

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.637

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

Storage

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

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