Drug Drug Interactions

There was no evidence of drug-drug interactions when Zelmac was co-administered with any of the following:– Warfarin.

– Low-dose oral triphasic contraceptives.

– Digoxin.

– Theophylline.

– Dextromethorphan.

Warfarin:

The effects of multiple doses of Zelmac on the pharmacokinetics and pharmacodynamics of R- and S- warfarin were investigated in an open-label, randomized, two-period, crossover study involving 12 healthy subjects.

The subjects were aged between 21 and 40 years. They were randomized to one of two treatment sequences: period 1, warfarin 30 mg alone on Day 4, then period 2, Zelmac 6 mg b.i.d. during Days 1-7 plus warfarin 30 mg on Day 4, or period 1, Zelmac during Days 1-7 plus warfarin on Day 4, then period 2, warfarin alone on Day 4. Prothrombin times were monitored up to 168 hours after each dose of warfarin. There was a 21-day interval between the two-warfarin doses.

The pharmacokinetic profiles of R- and S-warfarin were similar with and without Zelmac.

Furthermore, no significant differences in average or maximal prothrombins time (from 0 to 168 hours post-dose) were found when Zelmac was co-administered with warfarin (compared to treatment with warfarin alone).

Thus, during co-administration of Zelmac, no warfarin dose adjustment is required.

Low-dose oral triphasic contraceptives:

A study was conducted to determine the effect of Zelmac on the pharmacokinetics of ethinylestradiol and lovonorgestrel in 45 healthy women who were receiving a triphasic oral contraceptive.

A double-blind, randomized, placebo-controlled, crossover design was employed as add-on medication during the last two periods of this three-period study, conducted over three consecutive 28-day menstrual cycles. During the first cycle all subjects took only the oral contraceptive, then during the next two cycles subjects received either Zelmac 6 mg b.i.d. or matched placebo in addition to the oral contraceptive. During the third cycle each subject received whichever add-on medication she has not received during the second cycle.

Co-administration of Zelmac did not affect systemic exposure to ethinylestradiol; AUC0-12 hours and Cmax,85 values with Zelmac were comparable to those seen with placebo.

Systemic exposure to levonorgestrel was slightly decreased when Zelmac was co-administered with the oral contraceptive. However, this change (8%) was unlikely to be clinically relevant.

There was, thus, no evidence of any increased risk of ovulation if Zelmac was taken with oral contraceptives.

Digoxin:

Digoxin is a potent inotropic agent with a narrow therapeutic index. It is, therefore, important to be aware of any drug-drug interactions that may affect plasma concentrations of digoxin. In a randomized, open-label, two-period, crossover study, 12 healthy subjects received a single oral 1 mg dose of digoxin in one period and during the other period, oral doses of Zelmac 6 mg b.i.d. for 5 days plus a single oral dose of 1 mg digoxin on Day 4. The plasma concentrations of digoxin were measured during both treatment periods.

– The elimination half-life was similar whether digoxin was given alone (46.0±5.5 hours) or co-administered with Zelmac (46.3±8.3 hours). AUC, Cmax and C65 min (predicted steady-state trough concentrations) were reduced when digoxin was co-administered with Zelmac. These decreases are unlikely to be clinically relevant, but should be considered if the patient is not responding to digoxin therapy.

– The pharmacodynamics of digoxin during co-administration with Zelmac was also assessed. No alterations in ventricular rate or QT interval were observed. Thus, the dose of digoxin should not generally require adjustment during co-administration with Zelmac.

Theophylline:

(Used in the treatment of asthma and a prototype substrate for the CYP1A2 enzymes metabolizing caffeine estradiot, antiarrhythmics and muscle relaxants).

Eighteen healthy subjects were randomized to receive either a single dose of a controlled release formulation of theophyline 600 mg on Day 1, or Zelmac 6 mg on Day 1 and concomitant administration of Zelmac 6 mg and theophylline 600 mg on the morning of Day 2, followed 12 hours later by an additional dose of Zelmac 6 mg. Each subject then received the alternative treatment regimen 4-10 days later.

The pharmacokinetic parameters of theophylline, AUC, Cmax and T1/2 were similar during the two treatment regimens, but a statistically significant reduction in the Tmax of theophylline was observed when Zelmac was co-administered. Renal clearance of theophylline and partial metabolite formation clearances of 1.3-dimethyluric acid and 3-methylaxanthine were not significantly affected by co-administration with Zelmac. A statistically significant reduction in partial metabolite formation clearance from theophylline to 1-methyluric acid was observed when Zelmac was co-administered. However, this is unlikely to be clinically relevant.

Thus, the dose of theophylline does not require adjustment when Zelmac is co-administered. Furthermore, the lack of pharmacokinetic interaction between theophylline and Zelmac suggests that no dose adjustment is likely to be required when Zelmac is co-administered with other drugs that are CYP1A2 substrates.

Dextromethorphan:

(prototype substrate for CYP2D6 enzymes setabolizing a number of psychotropic and cardiovascular drugs, e.g. fluoxeline and omeparzole).

– A randomized, open-label, two-period, crossover study was conducted to determine the effects of multiple doses of Zelmac on the pharmacokinetics of dextromethorphan and its CYP2D6-mediated metabolite, dextrorphan, in healthy subjects.

– Eighteen healthy subjects, who were extensive metabolizers of CYP2D6, were randomized to receive either a single dose of dextromethorphan 120 mg after an overnight fast, or Zelmac 6 mg b.i.d. on Days 1 and 2 of the study, and a single dose of dextromethorphan 120 mg 1 hour after the morning dose of Zelmac on Day 2. After 7 days, each subject then received whichever treatment he/she had not received during the first period. Blood samples were taken for 24 hours after each dose of dextromethorphan and for 12 hours after the morning doses of Zelmac.

– The values for Cmax1 AUC1-∞ and Tmax were similar with and without Zelmac co-administration, indicating that Zelmac did not alter the rate of absorption of dextromethorphan. The estimated clearance of dextromethorphan was also similar for the two treatments, suggesting that Zelmac did not alter the metabolic elimination of dextropethorphan.

– The lack of interaction between Zelmac and dextromethorphan suggests that it is unlikely that other CYP2D6 substrates will be affected by co-administration of Zelmac.