Miconazole dosing

Miconazole. Miconazole nitrate [22832-87-7] (Fig. 2), the 1-phenethyl-imidazole derivative first described in 1969, interferes at low doses with the cytochrome P-450 dependent ergosterol biosynthesis in yeasts and fungi. The result is accumulation of C-14 methylated sterols on the one hand and reduction of the ergosterol levels in the membranes on the other hand (12). Analogous to clotrimazole, this leads to a disturbance in the membranes it results in inhibition of ceU repHcation, mycelium development (in C. albicans) and finally, ceU death. High concentrations of miconazole, which may be achieved with topical use, disturb the orientation of phosphoHpids in the membranes, which produces leaks (13). 

Plasma levels of 3—5 p.g/mL are obtained two hours after adraiinistration of 200 mg ketoconazole. No accumulation in the bloodstream was noted after a 30-wk treatment with this dose. The half-life is approximately eight hours. When ketoconazole is taken with meals, higher plasma levels are obtained. Distribution studies using radioactive ketoconazole in rats show radioactivity mainly in the Hver and the connective tissue. Radioactivity is also present in the subcutaneous tissue and the sebaceous glands. After one dose of 200 mg in humans, ketoconazole is found in urine, saUva, sebum, and cenimen. Like miconazole, the mode of action is based on inhibition of the cytochrome P-450 dependent biosynthesis of ergosterol. This results in disturbed membrane permeabiUty and membrane-bound enzymes (8,10,23,25). 

Miconazole is an imidazole antifungal agent used as miconazole base or miconazole nitrate for the treatment of superficial candidiasis and of skin infections dermato-phytosis and pityriasis versicolor. The drug has also been given intravenously by infusion for the treatment of disseminated fungal infections. Miconazole can be given by mouth in a dose of 120-240 mg, as oral gel four times daily after food, for... 

Intravenous doses of miconazole have ranged from 0.2 g daily to 1.2 g three times daily, depending on the sensitivity and severity of the infection. It should be diluted in sodium chloride 0.9% or glucose 5% and given by slow infusion the manufacturers recommend that daily dose up to 2.4 g should be diluted to a concentration of 1 mg/mL and infused at a rate of 100 mg/h, in order to reduce toxicity. Children over 1 year of age may be given 20-40 mg/kg body weight daily but not more than 15 mg/kg of miconazole should be given at each infusion [3]. 

Daneshmend [104] measured the serum concentration of miconazole in 11 healthy adult females for 72 h following a single 1200 mg vaginal pessary. The mean peak serum miconazole concentration was 10.4 pg/L and the mean elimination half-life was 56.8 h. The mean area under the serum concentration-time curve was 967 pg/L/h. The calculated mean systemic bioavailability of the vaginal pessary was 1.4%. There was large intersubject variation in serum miconazole pharmacokinetics. This formulation may provide effective single dose treatment for vaginal candidiasis. 

Ohzawa et al. [Ill] studied the metabolism of miconazole after a single oral or intravenous administration of 14C miconazole at a dose of 10 mg/kg. After 1 h oral or intravenous administration to male rats, the four known metabolites besides the unchanged form were observed in the plasma, and the five unknown metabolites were observed in the plasma. At 24 h, metabolites were not detected in plasma except one of the known metabolites. After oral administration to female rats, the unchanged form and four of the known metabolite along with one of the unknown metabolites were observed in the plasma, but one of the known metabolites and three of the unknown metabolites were not detected. After oral or intravenous administration to male rats, two of the known metabolites and five of the unknown metabolites were observed in the urine collected until 24 h. After oral or intravenous administration to male rats, four of the known metabolites and five of the unknown metabolites and one of the known metabolites besides the unchanged form were observed in the feces collected until 24 h. The fecal excretion of the major known metabolite, within 24 h after oral or intravenous administration was 19.4% or 13.3% of the administered radioactivity, respectively. One of the unknown metabolite was isolated from plasma after oral administration to female rats. 

Ohzawa et al [112] studied the absorption, distribution, and excretion of 14C miconazole in rats after a single administration. After the intravenous administration of 14C miconazole at a dose of 10 mg/kg to the male rats, the plasma concentration of radioactivity declined biophysically with half-lives of 0.76 h (a phase) and 10.32 h (/ phase). After oral administration of 14C miconazole at a dose of 1, 3, or 10 mg/kg to male rats, the plasma concentration of radioactivity reached the maximum level within 1.25 h, after dosing and the decline of radioactivity after the maximum level was similar to that after intravenous administration. At a dose of 30 mg/kg, the pharmacokinetic profile of radioactivity in the plasma was different from that at the lower doses. In the female rats, the plasma concentration of radioactivity declined more slowly than that in male rats. The tests were conducted on pregnant rats, lactating rats, bile-duct cumulated male rats. Enterohepatic circulation was observed. In the in situ experiment, 14C miconazole injected was observed from the duodenum, jejunum, and/or ileum, but not from the stomach. 

Ohzawa et al. [113] studied the absorption, excretion, and metabolism of miconazole after a single oral administration of 14C miconazole at a dose of 10 mg/kg to male dogs. After administration of 14C miconazole, the blood concentration of radioactivity reached the maximum level at 4 h, and then declined slowly with a half-life of about 26 h. The plasma concentration reached the maximum level at 5 h and then declined slowly with a half-life of 30 h. After the administration of miconazole, the plasma concentration of the unchanged form reached the maximum level at 3 h and then rapidly declined with half-life of about 4.3 h. Within 168 h after administration of 14C miconazole, urinary and fecal excretion amounted to about 6% and 66% of the administration radioactivity, respectively. After administration of 14C miconazole, the plasma concentration of the unchanged form rapidly declined, but the plasma level of two major metabolites reached maximum at 5 and 12 h, respectively and then declined. 

Ohzawa et al [114] studied the absorption, distribution, and excretion of 14C miconazole in male rats during and after consecutive oral administration at a dose of 10 mg/kg once a day for 15 days. During consecutive administration, the plasma concentration of radioactivity reached the steady state on day 4 and was 0.48 approximately 0.52 pg eq./mL at 24 h after each dose. After the final dose, the plasma concentration of radioactivity reached the maximum level of 1.67 pg eq./ mL at 7.5 h and declined with a half-life of about 18.68 h. The area under the curve 24 h was 28.3 pg h/mL, which is close to the area under the curve O-oo of a single oral dose. 

From 10 to 20% of an oral dose of miconazole is excreted in the urine, mainly as metabolites, within 6 days. About 50% of an oral dose may be excreted mainly unchanged in the feces. The elimination pharmacokinetics of miconazole have been described as triphasic, with a biological half-life of about 24 h. With an initial half-life of about 0.4 h, and intermediate half-life of about 2.5 h and elimination half-life of 24 h. Very little miconazole is removed by haemodialysis [3]. 

GI absorption of many poorly soluble drugs depends on small intestinal transit, as demonstrated for ketoprofen, nifedipine, haloperidol, miconazole, and others. Small intestinal transit rate and transit time become important factors in drug absorption, particularly when the ratio of dose to solubility is high and dissolution rate is very slow or when the drug is... 

A4 inhibitors - Patients receiving cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (erythromycin and clarithromycin), antifungal agents (ketoconazole, itraconazole, and miconazole), or cyclosporine or vinblastine should not receive doses of tolterodine greater than 1 mg twice/day (greater than 2 mg/day for ER capsules). 

Metabolism/Excretion— Miconazole is rapidly metabolized in the liver. About 14% to 22% of the administered dose is excreted in the urine, mainly as inactive metabolites. The terminal elimination half-life is 20 to 25 hours. 

T Pancreatic insulin release Metformin Peripheral insulin sensitivity hepatic glucose output/production i intestinal glucose absorption Dose Ist-line (naive pts), 1.25/250 mg PO daily-bid 2nd-line, 2.5/500 mg or 5/500 mg bid (max 20/2000 mg) take w/ meals, slowly T dose hold before 48 h after ionic contrast media Caution [C, -] Contra SCr >1.4 mg/dL in females or >1.5 mg/dL in males hypoxemic conditions (sepsis, recent MI) alcoholism metabolic acidosis liver Dz Disp Tabs SE HA, hypoglycemia, lactic acidosis, anorexia, N/V, rash Additional Interactions T Effects W/ amiloride, ciprofloxacin cimetidine, digoxin, miconazole, morphine, nifedipine, procainamide, quinidine, quinine, ranitidine, triamterene,... 

Brown, D., Henzl, M. R., and Kaufman, R. H. (1999), Butoconazole nitrate 2% for vulvovaginal candidiasis. New, single-dose vaginal cream formulation vs. seven-day treatment with miconazole nitrate. Gynazole 1 Study Group, /. Reprod. Med., 44, 933-938. 

CARBAMAZEPINE ANTIFUNGALS - ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, POSACONAZOLE, VORICONAZOLE 1 plasma concentrations of itraconazole and of its active metabolite, ketoconazole, posaconazole and voriconazole, with risk of therapeutic failure, t carbamazepine plasma concentrations These azoles are highly lipophilic, and clearance is heavily dependent upon metabolism by CYP isoenzymes. Carbamazepine is a powerful inducer of CYP3A4 and other CYP isoenzymes (CYP2C18/19, CYP1A2), and the result is very low or undetectable plasma levels. Inhibition of P-gp t bioavailability of carbamazepine Avoid co-administration of posaconazole or voriconazole with carbamazepine. Watch for inadequate therapeutic effects, and t dose of itraconazole. Higher doses of itraconazole may not overcome this interaction. Consider use of the less lipophilic fluconazole, which is less dependent on CYP metabolism. Necessary to monitor carbamazepine levels... 

ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, FLUCONAZOLE, VORICONAZOLE TCAs Possible t plasma concentrations of TCAs All TCAs are metabolized primarily by CYP2D6. Other pathways include CYP1A2 (e.g. amitriptyline, clomipramine, imipramine), CYP2C9 and CYP2C19(e.g. clomipramine, imipramine). Ketoconazole and voriconazole are documented inhibitors of CYP2C19. Fluconazole and voriconazole are reported to inhibit CYP2C9 Warn patients to report t side-effects of TCAs such as dry mouth, blurred vision and constipation, which may be an early sign of t TCA levels. In this case, consider 1 dose of TCA... 

ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, POSACONAZOLE H2 RECEPTOR BLOCKERS 1 plasma concentrations and risk of treatment failure 1 absorption of these antifungals as t gastric pH Avoid concomitant use. If unable to avoid combination, take H2 blockers at least 2-3 hours after the antifungal. Use an alternative antifungal or separate doses by at least 2 hours and give with an acidic drink, e.g. a carbonated drink t dose of antifungal may be required... 

Among the imidazole derivatives, numerous case reports or studies have shown that ketoconazole, fluconazole, and itraconazole can inhibit ciclosporin metabolism and increase blood ciclosporin concentrations (267). Ketoconazole, which is undoubtedly the most potent inhibitor, has been used to reduce the dose, and therefore the cost or adverse effects, of ciclosporin (268-270). There was also a beneficial effect on the rate of rejection or infection. In contrast, interactions with metronidazole and miconazole have only been described in isolated case histories (SEDA-19, 351) (5). 

Econazole is the deschloro derivative of miconazole. Econazole readily penetrates the stratum comeum and achieves effective concentrations down to the mid-dermis. Less than 1% of an applied dose is absorbed into the blood. Approximately 3% of recipients have local erythema, burning, stinging, or itching. Econazole nitrate (spectazoie, others) is available as a water-miscible cream (1%) to be applied twice a day. 

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