| Section 4.2
Information on dosing in children, elderly, hepatic and renal impairment has been updated
Added ‘A decrease in side-effects (increase of the resorption and decrease of the peak plasma concentration) can be reached by taking Molipaxin after a meal.’
Section 4.3
Added contraindications in Alcohol intoxication and intoxication with hypnotics and Acute myocardial infarction.
Section 4.4
Added warning on Use in children and adolescents under 18:
Molipaxin should not be used in children and adolescents under 18 years old. Suicidal behaviour (suicidal attempt and suicidal planning) and hostility (essentially aggressiveness, opposing behavior and anger) has been observed in a clinical study on children and adolescents treated with antidepressant more frequently than with placebo. Moreover, long-term safety data on children and adolescents regarding growth, maturation and cognitive and behavioral development are not available.
Removed ‘Molipaxin should be administered with care in patients with severe hepatic, renal or cardiac disease.
Care should be exercised when administering Molipaxin to patients suffering epilepsy, avoiding in particular, abrupt increases or decreases in dosage’
The following text was added:
‘To minimise the potential risk of suicide attempts, particularly at therapy initiation, only restricted quantities of Molipaxin should be prescribed at each occasion.
It is recommended that careful dosing and regular monitoring is adopted in patients with the following conditions:
• Epilepsy, specifically abrupt increases or decreases of dosage should be avoided
• Patients with hepatic or renal impairment, particulary if severe
• Patients with cardiac disease, such as angina pectoris, conduction disorders or AV blocks of different degree, recent myocardial infarction
• Hyperthyroidism
• Micturition disorders, such as prostate hypertrophy, although problems would not be anticipated as the anticholinergic effect of Molipaxin is only minor
• Acute narrow angle glaucoma, raised intra-ocular pressure, although major changes would not be anticipated due to the minor anticholinergic effect of Molipaxin
Should jaundice occur in a patient, Molipaxin therapy must be withdrawn.
Administration of antidepressants in patients with schizophrenia or other psychotic disorders may result in a possible worsening of psychotic symptoms. Paranoid thoughts may be intensified. During therapy with Molipaxin a depressive phase can change from a manic – depressive psychosis into a manic phase. In that case Molipaxin must be stopped.
Interactions in terms of serotonine syndrome/malignant neuroleptic syndrome have been described in case of concomitant use of other serotonergically acting substances like other antidepressants (e.g. tricyclic antidepressants, SSRI’s, SNRI’s and MAO-inhibitors) and neuroleptics. Malignant neuroleptic syndromes with fatal outcome have been reported in cases of coadministration with neuroleptics, for which this syndrome is a known possible adverse drug reaction. See Sections 4.5 and 4.8 for further information.
Since agranulocytosis may clinically reveal itself with influenza-like symptoms, sore throat, and fever, in these cases it is recommended to check haematology.
Hypotension, including orthostatic hypotension and syncope, has been reported to occur in patients receiving Molipaxin. Concomitant administration of antihypertensive therapy with Molipaxin may require a reduction in the dose of the antihypertensive drug
Elderly patients are often more sensitive to antidepressants, in particular to orthostatic hypotension and other anticholinergic effects.
Following therapy with Molipaxin, particularly for a prolonged period, an incremental dosage reduction to withdrawal is recommended, to minimise the occurrence of withdrawal syptoms, characterised by nausea, headache, and malaise.
There is no evidence that Molipaxin hydrochloride possesses any addictive properties.
As with other antidepressant drugs, cases of QT interval prolongation have been reported with Molipaxin very rarely. Caution is advised when prescribing Molipaxin with medicinal products known to prolong QT interval. Molipaxin should be used with caution in patients with known cardiovascular disease including those associated with prolongation of the QT interval.
As with other drugs with alpha-adrenolytic activity, Molipaxin has very rarely been associated with priapism. This may be treated with an intracavernosum injection of an alpha-adrenergic agent such as adrenaline or metaraminol. However there are reports of Molipaxin-induced priapism which have required surgical intervention or led to permanent sexual dysfunction. Patients developing this suspected adverse reaction should cease Molipaxin immediately.
Section 4.5
Minor updates to wording of existing text. Added the following: ‘General: The sedative effects of antipsychotics, hypnotics, sedatives, anxiolytics, and antihistaminic drugs may be intensified; dosage reduction is recommended in such instances.
The metabolism of antidepressants is accelerated due to hepatic effects by oral contraceptives, phenytoin, carbamazepine and barbiturates. The metabolism of antidepressants is inhibited by cimetidine and some other antipsychotics.
It has been confirmed in in- vivo-studies in healthy volunteers, that a ritonavir dose of 200 mg BID increased the plasma levels of Molipaxin by greater than two-fold, leading to nausea, syncope and hypotension.
Concomitant use of carbamazepine 400 mg daily led to a decrease of plasma concentrations of trazadone and its active metabolite m-chlorophenylpiperazine of 76 % and 60 %, respectively
Molipaxin intensifies the sedative effects of alcohol. Alcohol should be avoided during Molipaxin therapy.
Antidepressants can accelerate the metabolism of levodopa.
Tricyclic antidepressants: concurrent administration should be avoided due to the risk of interaction. Serotonine syndrome and cardiovascular side effects should be bewared.
Fluoxetine: rare cases have been reported of elevated Molipaxin plasma levels and adverse effects when Molipaxin had been combined with fluoxetine, a CYP1A2/2D6 inhibitor. The mechanism underlying a pharmacokinetic interaction is not fully understood. A pharmacodynamic interaction (serotonine syndrome) could not be excluded.
Phenothiazines: Severe orthostatic hypotension has been observed in case of concomitant use of phenothiazines, like e.g. chlorpromazine, fluphenazine, levomepromazine, perphenazine.
Other
Concomitant use of Molipaxin with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Caution should be used when these drugs are coadministered with Molipaxin.
Undesirable effects may be more frequent when Molipaxin is administered together with preparations containing Hypericum perforatum (St Johns wort).
There have been reports of changes in prothrombin time in patients concomitantly receiving trazodone and warfarin.
Section 4.6:
Replaced the existing text with the following: Pregnancy:
Data on a limited number (< 200) of exposed pregnancies indicate no adverse effects of Molipaxin on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data area available. The safety of Molipaxin in human pregnancy has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development at therapeutic doses. On basic principles, therefore, its use during the first trimester should be avoided.
Caution should be exercised when prescribing to pregnant women. When Molipaxin is used until delivery, newborns should be monitored for the occurrence of withdrawal symptoms.
Lactation:
Limited data indicate that excretion of Molipaxin in human breast milk is low, but levels of the active metabolite are not known. Due to the paucity of data, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Molipaxin should be made taking into account the benefit of breast-feeding to the child and the benefit of Molipaxin therapy to the woman.
Section 4.7: Rephrased and added additional information
Section 4.8: Adverse events have been tabulated
Section 4.9: Correction of typographical error
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