in the everolimus-treated group.
One risk factor for severe renal impairment in LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting. Active management of diarrhea and any other gastrointestinal symptoms should be initiated for Grade 1 events.
Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment [see DOSAGE AND ADMINISTRATION (2.4)].
5.8 Gastrointestinal Perforation and Fistula Formation
In Study 1 in DTC, events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and 0.8% of patients in the placebo group.
In Study 2 in RCC, Grade 3 or greater gastrointestinal perforation, abscess or fistula was reported in 2% of patients in the LENVIMA + everolimus-treated group and no patients in the everolimus-treated group. The events resolved in all patients.
Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula [see DOSAGE AND ADMINISTRATION (2.4)].
5.9 QT Interval Prolongation
In Study 1 in DTC, QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of greater than 500 ms was 2% in LENVIMA-treated patients compared to no reports in the placebo group.
In Study 2 in RCC, QTc interval increases greater than 60 ms were reported in 11% of patients in the LENVIMA + everolimus-treated group. The incidence of QTc interval greater than 500 ms was 6% in the LENVIMA + everolimus-treated group. No reports of QTc interval prolongation greater than 500 ms or increase greater than 60 ms occurred in the everolimus-treated group.
Monitor and correct electrolyte abnormalities in all patients. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold LENVIMA for the development of QTc interval prolongation greater than 500 ms. Resume LENVIMA at a reduced dose when QTc prolongation resolves to baseline [see DOSAGE AND ADMINISTRATION (2.4), CLINICAL PHARMACOLOGY (12.2)].
5.10 Hypocalcemia
In Study 1 in DTC, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction.
In Study 2 in RCC, 6% of patients in the LENVIMA + everolimus-treated group and 2% of patients in the everolimus-treated group experienced Grade 3 or greater hypocalcemia. No patients discontinued due to hypocalcemia [see ADVERSE REACTIONS (6.1)].
Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia [see DOSAGE AND ADMINISTRATION (2.4)].
5.11 Reversible Posterior Leukoencephalopathy Syndrome
Across clinical studies in which 1160 patients received LENVIMA monotherapy, there were 4 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resol |
