TOLSURA- itraconazole capsule, gelatin coated

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

ITRACONAZOLE (UNII: 304NUG5GF4) (ITRACONAZOLE - UNII:304NUG5GF4)

Available from:

Mayne Pharma Commercial LLC

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

TOLSURA is indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised adult patients: - Blastomycosis, pulmonary and extrapulmonary - Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and - Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-fungal therapy should be adjusted accordingly Limitations of Use: TOLSURA is not indicated for the treatment of onychomycosis. TOLSURA is NOT interchangeable or substitutable with other itraconazole products due to the differences in the dosing between TOLSURA and other itraconazole products. Therefore, follow the specific dosage recommendations for TOLSURA [see Dosage and Administration (2)]. - Co-administration of certain drugs that are metabolized by human CYP3A4 substrates are contraindicated with TOLSURA because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs [see Warnings and Precaution (5.4)and Drug Interactions (7.1)] . - Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment. - Co-administration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors [see Drug Interactions (7.1)] . - Increased plasma concentrations of some of these drugs due to co-administration of TOLSURA can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes , a potentially fatal arrhythmia [ see Drug Interactions (7.1)] . TOLSURA is contraindicated in patients with known hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents [see Warnings and Precautions (5.7)] . Risk Summary There are no data on exposure to itraconazole during pregnancy for the approved indications. Published epidemiologic studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy have reported no risk of major birth defects overall and inconclusive findings on the risk of miscarriage (see Data) . In animal reproduction studies, itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately (6-25 times the maximum recommended human dose [MRHD] of 390 mg/day based on mg/kg comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (12 times the MRHD). All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Published prospective and retrospective cohort studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy (sample size 198-687) have reported no increase in the rate of major birth defects. The most important methodological limitation of these studies is the short duration of exposure in pregnancy (mean duration 6.9 to 8.5 days), or the lack of information on treatment duration. The risk of prolonged exposure in pregnancy is not known. Published prospective and retrospective cohort studies of pregnant women exposed to itraconazole (sample size 131-198) have reported inconsistent findings on the risk of miscarriage. Available data are inconclusive and limited by possible bias due to earlier enrollment and possible residual confounding in the exposed group compared to the unexposed group. Animal Data Itraconazole has been shown to cross the placenta in a rat model. In animal reproduction studies, itraconazole administration to rats and mice during organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity at and above 40 and 80 mg/kg respectively (doses equivalent to 6- and 12-times the MRHD of 390 mg/day, based on mg/kg comparisons). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. Risk Summary Itraconazole is excreted in human milk; however, there are no data on the amount of itraconazole in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TOLSURA and any potential adverse effects on the breastfed child from TOLSURA or from the underlying maternal condition. Safety and effectiveness in pediatric patients have not been established. The long-term effects of itraconazole on bone growth in children are unknown. Bone lesions were observed in the young adult rats dosed with oral itraconazole for 3 to 12 months [see Nonclinical Toxicology (13.2)] . Clinical studies of itraconazole did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. It is advised to use TOLSURA Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Reversible or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated [see Boxed Warning, Contraindications (4.1) and Drug Interactions (7.1)] . Limited data are available on the use of oral itraconazole in patients with renal impairment. It is recommended that patients with renal impairment be carefully monitored when taking TOLSURA [see Clinical Pharmacology (12)and Warnings and Precautions (5.1)] . Limited data are available on the use of oral itraconazole in patients with hepatic impairment. It is recommended that patients with impaired hepatic function be carefully monitored when taking TOLSURA. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4 [see Clinical Pharmacology (12.3)] . In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with TOLSURA is strongly discouraged unless 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 hepatic function abnormalities or those who have experienced liver toxicity with other medications [see Clinical Pharmacology (12)and Warnings and Precautions (5.2)].

Product summary:

TOLSURA (itraconazole capsules) is supplied in a size 1, hard gelatin capsules with light blue cap and white body, imprinted with "i-65" in black on the cap and containing 65 mg of itraconazole. TOLSURA capsules are supplied as follows: Store at 25°C (77°F); excursions permitted 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light resistant container.

Authorization status:

New Drug Application

Summary of Product characteristics

TOLSURA- ITRACONAZOLE CAPSULE, GELATIN COATED
MAYNE PHARMA COMMERCIAL LLC
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
TOLSURA
SAFELY AND
EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR TOLSURA
.
TOLSURA
(ITRACONAZOLE CAPSULES), FOR ORAL USE
INITIAL U.S. APPROVAL: 1992
WARNING: CONGESTIVE HEART FAILURE AND DRUG INTERACTIONS
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
CONGESTIVE HEART FAILURE
TOLSURA CAN CAUSE OR EXACERBATE CONGESTIVE HEART FAILURE (CHF). WHEN
ITRACONAZOLE
WAS ADMINISTERED INTRAVENOUSLY TO HEALTHY HUMAN VOLUNTEERS AND DOGS,
NEGATIVE
INOTROPIC EFFECTS WERE SEEN. IF SIGNS OR SYMPTOMS OF CONGESTIVE HEART
FAILURE OCCUR
OR WORSEN DURING ADMINISTRATION OF TOLSURA, REASSESS THE BENEFIT-RISK
OF CONTINUING
TREATMENT. ( 5.1, 6).
DRUG INTERACTIONS
CO-ADMINISTRATION OF CERTAIN DRUGS THAT ARE METABOLIZED BY HUMAN
CYP3A4
ENZYMES ARE CONTRAINDICATED WITH TOLSURA BECAUSE PLASMA CONCENTRATIONS
OF
SUCH DRUGS ARE INCREASED. ( 4.1, 5.4, 7.1)
CO-ADMINISTRATION WITH COLCHICINE, FESOTERODINE AND SOLIFENACIN IS
CONTRAINDICATED
IN SUBJECTS WITH VARYING DEGREES OF RENAL OR HEPATIC IMPAIRMENT. (
4.1, 7.1)
CO-ADMINISTRATION WITH ELIGLUSTAT IS CONTRAINDICATED IN POOR OR
INTERMEDIATE
METABOLIZERS OF CYP2D6 AND IN SUBJECTS TAKING STRONG OR MODERATE
CYP2D6
INHIBITORS. ( 4.1, 7.1)
INCREASED PLASMA CONCENTRATIONS OF SOME OF THESE DRUGS CAN LEAD TO QT
PROLONGATION AND VENTRICULAR TACHYARRHYTHMIAS INCLUDING OCCURRENCES OF
TORSADES
DE POINTES, A POTENTIALLY FATAL ARRHYTHMIA. ( 4.1, 5.4, 7.1)
INDICATIONS AND USAGE
TOLSURA is an azole antifungal indicated for the treatment of the
following fungal infections in
immunocompromised and non-immunocompromisedadult patients ( 1):
Blastomycosis, pulmonary and extrapulmonary
Histoplasmosis, including chronic cavitary pulmonary disease and
disseminated, non-meningeal
histoplasmosis, and
Aspergillosis, pulmonary and extrapulmonary, in patients who are
intolerant of or who are refractory to
amphotericin B th