Drug Interactions between estradiol / norethindrone / relugolix and tizanidine

GENERALLY AVOID: Coadministration with oral contraceptives may significantly increase the plasma concentrations and pharmacologic effects of tizanidine. The proposed mechanism is inhibition of tizanidine metabolism via CYP450 1A2. Retrospective evaluation of population pharmacokinetic data following single- and multiple-dose administration of tizanidine revealed an approximately 50% decrease in the clearance of tizanidine in women receiving oral contraceptives compared to women not receiving oral contraceptives. In a study of 30 healthy volunteers administered a single 4 mg dose of tizanidine, mean peak plasma concentration (Cmax) of tizanidine was 3.0 times higher and mean area under the plasma concentration-time curve (AUC) was 3.9 times greater in women using an oral contraceptive containing ethinyl estradiol and gestodene than in women not on the contraceptive. In one contraceptive user, the tizanidine AUC exceeded the mean AUC of the control subjects by nearly 20 times. There were no significant differences in the elimination half-life or time to peak concentration in plasma (Tmax) of tizanidine between the groups. Tizanidine to metabolite ratios in plasma and urine were 2 to 10 times higher in the contraceptive users than in control subjects, and the excretion of unchanged tizanidine into urine was on average 3.8 times greater in the contraceptive group. In addition, both the systolic and diastolic blood pressures were lowered by tizanidine more in the contraceptive users (29 mmHg and 21 mm Hg, respectively) than in the control subjects (17 mmHg and 13 mmHg, respectively). The interaction has also been reported with other CYP450 1A2 inhibitors such as fluvoxamine, ciprofloxacin, and rofecoxib.

MANAGEMENT: The use of tizanidine in combination with oral contraceptives or other CYP450 1A2 inhibitors should generally be avoided. Caution is advised if concurrent use is clinically necessary. Dosage adjustments may be required in patients who experience excessive adverse effects of tizanidine such as drowsiness, dizziness, lightheadedness, hypotension, bradycardia, or syncope.

GENERALLY AVOID: Long-term androgen deprivation therapy (ADT) can prolong the QT interval. Coadministration of ADT with other agents that may prolong the QT interval could also result in additive effects and an increased risk of ventricular arrhythmias including torsade de pointes and sudden death. The risk may be increased in patients with certain underlying risk factors like congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). Studies in young men have shown that endogenous serum testosterone levels are inversely associated with QTc (QT interval corrected for heart rate) duration. Clinical trials in men with low serum testosterone levels have reported testosterone administration being associated with a shortening of QTc. Likewise, studies using ADT have shown that it may prolong the QT interval; however, this effect may vary by drug, dose, or even each drug class that can be used to reduce testosterone levels. A clinical study comparing abarelix to a luteinizing hormone-releasing hormone agonist plus nonsteroidal antiandrogen therapy found that both therapies prolonged the mean Fridericia-corrected QT interval (QTcF) by more than 10 msec from baseline. Approximately 20% of patients in both groups had either changes from baseline QTc of >30 msec or end-of-treatment QTc values >450 msec. Similarly, a study comparing degarelix to leuprolide found that approximately 20% of patients on each drug had QT/QTc intervals >450 msec after 1 year of treatment. From baseline to end of study, the median change in QTcF was 12.3 msec for degarelix and 16.7 msec for leuprolide. Some drugs used to lower testosterone levels may also have other side effects that can predispose a patient to QT prolongation and torsade de pointes. For example, inhibitors of 17 alpha-hydroxylase/C17,20-lyase (CYP17) like abiraterone may cause hypokalemia as a result of increased mineralocorticoid levels. Clinical data on ADT prolonging the QT interval in women and children are lacking.

MANAGEMENT: The benefits of androgen deprivation therapy (ADT) should be carefully assessed against the potential risk in patients receiving other drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected prior to initiating therapy, and monitoring of electrocardiograms and electrolytes may be advisable. The manufacturer's labeling as well as current clinical guidelines should be consulted for monitoring recommendations.