- A study found no evidence of drug interactions between Zelmac and several other drugs including warfarin, oral contraceptives, digoxin, theophylline, and dextromethorphan. - Pharmacokinetic profiles of warfarin, exposure to contraceptive hormones, and pharmacokinetics of digoxin, theophylline, and dextromethorphan were unaffected or showed minor changes unlikely to be clinically significant when taken with Zelmac. - Based on these studies, doses of these drugs generally do not require adjustment when taken with Zelmac.

1. 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.

2. 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.

3.  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.

4. 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.

5.  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.

6. 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.

7. – 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.

8. 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.

9.  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.

10. 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.

11. – 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.