Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamics
The mechanism of action is still unclear. According to experimental findings in animals, the re-uptake inhibition of the monoaminergic neurotransmitters noradrenalin, serotonin and dopamine into the pre- synaptic neurons is discussed. Also, there is in-vitro data on a down- regulation of central beta-adrenoreceptors. The clinical effect is attributed to the increase of neurotransmitter concentration in the synaptic cleft and to the modulating effect of the neurotransmitters at the postsynaptic membrane.

Clinical efficacy
The study data described below do not refer to the licensed field of application mood swings for Remotiv 250/ Remotiv 500, but were obtained with the treatment of minor and moderate depressive episodes, and are intended as background information for appropriate dispensing and administration.

In a double-blind, randomized, placebo-controlled, multi-centre study with two-arms, efficacy and safety of the active substance Ze 117 (2 x 250 mg/ day) were investigated in 162 patients for the treatment of minor and moderate depressive episodes (ICD-10/F32.0 and F32.1) compared to placebo. The HAMD-21 score (Hamilton Score of Depression) had to be between 16 and 24 points at the beginning of the study. The score was reduced in the active substance group (Ze 117; n = 81 patients) from an initial average of 20.13 points (95% confidence interval   (CI):    19.50 - 20.76 points)   to   10.53 points   (95%   CI: 9.28 - 11.78 points), and in the placebo group (n = 81 patients) from an initial point value of 18.76 (95% CI: 17.88 - 19.45 points) to 17.89 points (95% CI: 16.51 - 19.28 points) (p < 0.0001). The responder rates were 56% in the active substance group and 15% in the placebo group.

Thus, Ze 117 shows a statistically significant and clinically relevant superiority compared to placebo with respect to both decrease in HAMD score and responder rate. With respect to safety, the Ze 117 group demonstrated a side-effect rate which was comparable to the placebo group (Ze 117: n = 6 (7.4%) and placebo: n = 5 (6.2%)).

In a double-blind, randomized, controlled, multi-centre study with two arms, efficacy and safety of Ze 117 (2 x 250 mg/ day) were compared to the SSRI fluoxetine (20 mg/ day) over a period of 6 weeks in 240 patients with minor and moderate depressive episodes (ICD-10/F32.0 and F32.1).
The HAMD-21 score had to be between 16 and 24 points at the beginning of the study, and was reduced from almost identical initial score values of 19.6 to 11.5 in the Ze 117 group (n = 126 patients), and from 19.5 to 12.2 in the fluoxetine group (n = 114 patients). With these results the Ze 117 extract demonstrated in this study a comparable efficacy compared to fluoxetine (non-inferiority; p = 0.09). However, the responder rates were significantly higher in the Ze 117 group with 60% vs. 40% in the fluoxetine group (p = 0.005). Also, the tolerability profile of Ze 117 was more favourable than that of fluoxetine. Thus, 14% of the patients in the Ze 117 group experienced side-effects (of which a possible association with the study medication was found for 28% of the cases), compared to 25% of patients with side-effects in the fluoxetine group (72% of the cases with a possible association with the study medication) (p < 0.01).

In another double-blind, randomized, multi-centre study with two arms, efficacy and safety of Ze 117 (2 x 250 mg/ day; n = 157) were investigated in 324 patients for the treatment of minor and moderate depressive episodes (ICD-10/F32.0/1 and F33.0/1) compared to the tricyclic antidepressant imipramine (150 mg/ day, n = 167). Starting with almost identical initial values of 22.4 points (Ze 117) and 22.1 points (imipramine), the HAMD-17 score (Hamilton Score of Depression) was reduced to 12.0 points (Ze 117) and to 12.75 points (imipramine), respectively. With these results, a statistically comparable efficacy of Ze 117 versus imipramine (p = 0.20) with also comparable responder rates (43% in the Ze 117 group, and 40% in the imipramine group) was demonstrated.
With respect to safety, 39% of the patients in the Ze 117 group experienced side-effects compared to 63% of the patients in the imipramine group.

Other information

Clinical interaction study with a cocktail of 7 drugs and cytochrome P450 as well as the P-glycoprotein transporter:
In a clinical interaction study using St. John’s wort extract Ze 117 which is low in hyperforin and is contained in Remotiv 250/ Remotiv 500 film coated tablets, the influence on 7 drugs was investigated in 20 subjects.
The administration of St. John’s wort extract Ze 117 together with a cocktail of caffeine 50 mg (CYP1A2), bupropion·HCl 75 mg (CYP2B6), flurbiprofen 10 mg (CYP2C9), omeprazole 10 mg (CYP2C19), dextromethorphan 10 mg (CYP2D6), midazolam 1 mg (CYP3A4) and fexofenadine 25 mg (P-glycoprotein) did not show clinically relevant interactions in the pharmacokinetics of these drugs.

Clinical interaction studies with oral hormonal contraceptives and cytochrome P450:
A non-controlled clinical interaction study with the hyperforin-poor St. John’s wort extract Ze 117 (250 mg twice daily) which is contained in Remotiv 250/ Remotiv 500 film coated tablets and an oral hormonal contraceptive (0.02 mg ethinylestradiol and 0.15 mg desogestrel) in 16 healthy female subjects showed no negative influence on the pharmacokinetics of the active ingredients.

The average relative bioavailability rates of Cmax and AUC were elevated by about 10% after 14 days of Ze 117 intake; the confidence intervals of Cmax and AUC remained within the equivalence limits of 20%.    The    serum    concentrations    of    ethinyl   estradiol    and
3-ketodesogestrel were equivalent before and after 14 days of concomitant intake of Ze 117 and a hormonal oral contraceptive.
Clinical interaction study with digoxin and the PGP transporter: In a randomized, double-blind study, the inductive impact of hyperforin- poor St. John’s wort extract Ze 117 which is contained in Remotiv 250/ Remotiv 500 film coated tablets on the P-glycoprotein transporter was investigated in 17 healthy subjects. The pharmacokinetic parameters of digoxin were investigated in 7 subjects treated with Ze 117 and in 10 subjects treated with placebo. The subjects were adjusted to a steady- state digoxin trough level of 1.0 ng/ mg ± 20% and subsequently either received digoxin and Ze 117 concomitantly for 14 days, or digoxin and placebo, respectively. However, the respective AUC of digoxin in the placebo and verum groups showed no significant differences (p = 0.1460). The percentage change in digoxin trough level after 14 days of concomitant medication compared to Ze 117 baseline was tested for equivalence against the change with placebo. The one-sided t-test resulted in a p-value of 0.05, with which Ze 117 and placebo are equivalent in their influence on the digoxin trough level in the given range of ± 20%. The comparison of Ze 117 with placebo did not show any significant differences between the groups regarding the AUC changes.

Pharmacokinetic Properties

Pharmacokinetic properties
St. John's wort contains a number of phytochemical components, but hypericin is considered to be one of the main biological constituents. Hypericin can be used as a marker in order to determine the pharmacokinetics of the extract.
In male volunteers administered a Remotiv dose of 250mg and 500mg, peak plasma levels of hypericin were 0.67 mcg/l and 1.3mcg/l, respectively, at tmax values of 7.1 hours and 7.0 hours, respectively. The measured half-life values of hypericin were 21.4 hours and 24.6 hours, respectively. Following multiple bid dosing with 250 mg, mean hypericin plasma concentrations were 2.6 mcg/l. Steady state was achieved within 14 days without undue accumulation.

Clinical Trials
Remotiv has been shown to be as effective as fluoxetine and imipramine for the treatment of mild to moderate depression in short-term controlled clinical trials. Remotiv was associated with fewer adverse events in these trials. An open, 12-month study in 141 patients established the long-term safety of Remotiv. Remotiv maintained symptom improvement relative to baseline over this period. However, because there was no comparator arm, this study did not establish the long-term efficacy of the product.

Indications
For the treatment of symptoms of mild to moderate depression including dejected mood, mood lability, anxiety, inner restlessness, states of tension, and difficulty in falling asleep and sleeping through the night which is associated with these conditions. Treatment is recommended for up to 24 weeks.