ine and digoxin). Concomitant use of these drugs during MAYZENT initiation may be associated withsevere bradycardia and heart block.
o For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered beforeintroducing MAYZENT treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blockertreatment, MAYZENT can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blockertreatment should be interrupted until the baseline heart-rate is greater than 50 bpm. Treatment with MAYZENTcan then be initiated and treatment with a beta-blocker can be reinitiated after MAYZENT has been up-titrated tothe target maintenance dosage [see Drug Interactions (7.3)].
o For patients taking other drugs that decrease heart rate, treatment with MAYZENT should generally not beinitiated without consultation from a cardiologist because of the potential additive effect on heart rate [see Dosageand Administration (2.4) and Drug Interactions (7.2)].
Missed Dose During Treatment Initiation and Reinitiation of Therapy Following Interruption
If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiateDay 1 of the dose titration and follow titration monitoring recommendations [see Dosage and Administration (2.2, 2.3)].
5.4 Respiratory Effects
Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in MAYZENTtreatedpatients as early as 3 months after treatment initiation. In a placebo-controlled trial in adult patients, the decline inabsolute FEV1 from baseline compared to placebo was 88 mL [95% confidence interval (CI): 139, 37] at 2 years. Themean difference between MAYZENT-treated patients and patients receiving placebo in percent predicted FEV1 at 2 yearswas 2.8% (95% CI: -4.5, -1.0). There is insufficient information to determine the reversibility of the decrease in FEV1after drug discontinuation. In Study 1, five patients discontinued MAYZENT because of decreases in pulmonary functiontesting. MAYZENT has been tested in MS patients with mild to moderate asthma and chronic obstructive pulmonary
disease. The changes in FEV1 were similar in this subgroup compared with the overall population. Spirometric eva luationof respiratory function should be performed during therapy with MAYZENT if clinically indicated.
5.5 Liver Injury
Elevations of transaminases may occur in MAYZENT-treated patients. Recent (i.e., within last 6 months) transaminaseand bilirubin levels should be reviewed before initiation of MAYZENT therapy.
In Study 1, elevations in transaminases and bilirubin were observed in 10.1% of MAYZENT-treated patients compared to3.7% of patients receiving placebo, mainly because of transaminase [alanine aminotransferase/aspartateaminotransferase/gamma-glutamyltransferase (ALT/AST/GGT)] elevations.
In Study 1, ALT or AST increased to three and five times the upper limit of normal (ULN) in 5.6% and 1.4% ofMAYZENT-treated patients, respectively, compared to 1.5% and 0.5% of patients receiving placebo, respectively. ALTor AST increased eight and ten times ULN in MAYZENT-treated patients (0.5% and 0.2%, respectively) compared to nopatients receiving placebo. The majority of elevations occurred within 6 months of starting treatment. ALT levels returnedto normal within approximately 1 month after discontinuation of MAYZENT. In clinical trials, MAYZ |
