with history of uveitis or diabetes mellitus
Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during GILENYA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. The rate was approximately 20% in patients with a history of uveitis vs. 0.6% in those without a history of uveitis, in the combined experience with all doses of fingolimod. MS patients with diabetes mellitus or a history of uveitis should undergo an ophthalmologic eva luation prior to initiating GILENYA therapy and have regular follow-up ophthalmologic eva luations while receiving GILENYA therapy. GILENYA has not been tested in MS patients with diabetes mellitus.
5.4 Respiratory Effects
Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with GILENYA as early as 1 month after treatment initiation. At Month 24, the reduction from baseline in the percent of predicted values for FEV1 was 3.1% for GILENYA 0.5 mg and 2% for placebo. For DLCO, the reductions from baseline in percent of predicted values at Month 24 were 3.8% for GILENYA 0.5 mg and 2.7% for placebo. The changes in FEV1 appear to be reversible after treatment discontinuation. There is insufficient information to determine the reversibility of the decrease of DLCO after drug discontinuation. In MS controlled trials, dyspnea was reported in 5% of patients receiving GILENYA 0.5 mg and 4% of patients receiving placebo. Several patients discontinued GILENYA because of unexplained dyspnea during the extension (uncontrolled) studies. GILENYA has not been tested in MS patients with compromised respiratory function.
Spirometric eva luation of respiratory function and eva luation of DLCO should be performed during therapy with GILENYA if clinically indicated.
5.5 Hepatic Effects
Elevations of liver enzymes may occur in patients receiving GILENYA. Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of GILENYA therapy.
During clinical trials, 3-fold the upper limit of normal (ULN) or greater elevation in liver transaminases occurred in 8% of patients treated with GILENYA 0.5 mg, as compared to 2% of patients on placebo. Elevations 5-fold the ULN occurred in 2% of patients on GILENYA and 1% of patients on placebo. In clinical trials, GILENYA was discontinued if the elevation exceeded 5 times the ULN. Recurrence of liver transaminase elevations occurred with rechallenge in some patients, supporting a relationship to drug. The majority of elevations occurred within 6-9 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of GILENYA.
Liver enzymes should be monitored in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. GILENYA should be discontinued if significant liver injury is confirmed. Patients with pre-existing liver disease may be at increased risk of developing elevated liver enzymes when taking GILENYA.
Because GILENYA exposure is doubled in patients with severe hepatic impairment, these patients should be closely monitored, as the risk of adverse reactions is greater [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
5.6 Fetal Risk
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