“i-65” in black on the cap and containing 65 mg ofitraconazole.
4 CONTRAINDICATIONS
4.1 Drug Interactions
• Co-administration of certain drugs that are metabolized by human CYP3A4 substrates arecontraindicated with TOLSURA because plasma concentrations of such drugs are
increased, which may also increase or prolong both the pharmacologic effects and/oradverse reactions to these drugs [see Warnings and Precaution (5.4) and Drug
Interactions (7.1)].
• Co-administration with colchicine, fesoterodine and solifenacin is contraindicated insubjects with varying degrees of renal or hepatic impairment.
• Co-administration with eliglustat is contraindicated in subjects that are poor orintermediate 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 ofTOLSURA can lead to QT prolongation and ventricular tachyarrhythmias including
occurrences of torsade de pointes, a potentially fatal arrhythmia [see Drug Interactions(7.1)].
4.2 Hypersensitivity
TOLSURA is contraindicated in patients with known hypersensitivity to itraconazole. There islimited information regarding cross-hypersensitivity between itraconazole and other azoleantifungal agents [see Warnings and Precautions (5.7)].
5 WARNINGS AND PRECAUTIONS
5.1 Congestive Heart Failure
TOLSURA can cause or exacerbate congestive heart failure (CHF) [see Boxed Warning andAdverse Reactions (6.1)].
For patients with evidence of ventricular dysfunction such as CHF,history or risk factors for CHF, physicians should carefully review the risks and benefits ofTOLSURA therapy. These risk factors include cardiac disease such as ischemic and valvulardisease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renalfailure and other edematous disorders. Inform such patients of the signs and symptoms of CHFand monitor carefully for signs and symptoms of CHF during treatment. If signs or symptoms ofCHF appear or worsen during administration of TOLSURA, reassess the benefit-risk ofcontinuing treatment.
When itraconazole was administered intravenously to anesthetized dogs, a dose-related negativeinotropic effect was demonstrated. In a healthy volunteer study of itraconazole intravenousinfusion, transient, asymptomatic decreases in left ventricular ejection fraction were observedusing gated SPECT imaging; these resolved before the next infusion, 12 hours later.
Itraconazole has been associated with reports of CHF, peripheral edema, and pulmonary edema.
In post-marketing experience, heart failure was more frequently reported in patients receivinghigher total daily doses of itraconazole of 400 mg although there were also cases reported amongthose receiving lower total daily doses [see Adverse Reactions (6.2)].
Calcium channel blockers can have negative inotropic effects which may be additive to those ofitraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers.
Therefore, when co-administering itraconazole and calcium channel blockers, monitor carefullyfor signs and symptoms of CHF during treatment due to an increased risk of CHF. Concomitantadministration of TOLSURA and felodipine or nisoldipine is contraindicated [seeContraindications (4.1), Drug Interactions ( |
