nicalPharmacology (12.3)].
In patients with elevated or abnormal liver enzymes or active liver disease, or who haveexperienced liver toxicity with other drugs, treatment with TOLSURA is strongly discouragedunless there is a serious or life-threatening situation where the expected benefit exceeds the risk.
It is recommended that liver function monitoring be done in patients with pre-existing hepaticfunction abnormalities or those who have experienced liver toxicity with other medications [seeClinical Pharmacology (12) and Warnings and Precautions (5.2)].
10 OVERDOSAGE
Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportivemeasures should be employed. Activated charcoal may be given if considered appropriate.
11 DESCRIPTION
TOLSURA (itraconazole capsules) is an azole antifungal drug for oral use. Itraconazole is anequal mixture of four diastereomers (two enantiomeric pairs), each possessing three chiralcenters. It may be represented by the following structural formula and nomenclature:
(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ
2-1,2,4-triazolin-5-one
mixture with (±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one or (±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ
2-1,2,4-triazolin-5-one.
Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is awhite to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, andfreely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of valuesobtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 atpH 8.1.
Each TOLSURA capsule contains 65 mg of itraconazole dispersed in a polymer matrix andencapsulated in a hard gelatin capsule. The inactive ingredients are colloidal silicon dioxide,hypromellose phthalate, magnesium stearate and sodium starch glycolate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Itraconazole is an azole antifungal drug [see Microbiology (12.4)].
12.3 Pharmacokinetics
General Pharmacokinetic CharacteristicsThe steady-state pharmacokinetics of itraconazole following administration of a 130 mg twicedaily dose regimen of TOLSURA (2 x 65 mg) was compared with a 200 mg twice daily doseregimen of itraconazole capsules (2 x 100 mg) immediately after a meal for 14.5 days in 16healthy volunteers; the results from this study are presented in Table 6 below
Table 6: Pharmacokinetics of Itraconazole Following Administration of TOLSURA andItraconazole Capsules Given Twice Daily for 14.5 Days Under Fed Conditions1in 16 Healthy Subjects
Parameter2,3 TOLSURA 130 mg twice daily
(2 x 65 mg Capsules)
Itraconazole 200 mg twice daily
(2 x 100 mg Capsules)
AUC0-tau
(hr*mcg/ml)
15.6 ± 3.7 14.9 ±3.8
Ctrough
(mcg/ml)
1.2 ±0.4 1.0±0.3
Cmax,ss
(mcg/ml)
1.6 ±0.4 1.5 ±0.4
Tmax,ss
(h)
7.0 (1-10) 5.0 (1 |
