Anaphranil can reduce or completely eliminate the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine and alpha-methyldopa. Therefore, in cases when simultaneous administration of Anafranil requires the treatment of hypertension, other drugs should be used (eg, vasodilators or beta-blockers).
Tricyclic antidepressants, incl. Anaphranil, can potentiate the effect of anticholinergic drugs (eg, phenothiazines, antiparkinsonian drugs, atropine, biperiden, antihistamines) on the organ of vision, the central nervous system, the intestine and the bladder.
Tricyclic antidepressants can enhance the effects of ethanol and other agents that have a depressing effect on the central nervous system (eg, barbiturates, benzodiazepines, or anesthesia drugs).
Do not prescribe Anafranil for at least 2 weeks after the abolition of MAO inhibitors because of the risk of developing severe symptoms and conditions such as hypertensive crisis, fever, and symptoms of serotonin syndrome: myoclonus, agitation, seizures, delirium and coma. The same rule should be followed if the MAO inhibitor is prescribed after previous treatment with anaphranil. In either of these cases, the initial doses of Anafranil or MAO inhibitors should be low, they should be increased gradually, under the constant control of the effects of the drug.
Existing experience shows that Anafranil can be prescribed no earlier than 24 hours after the withdrawal of MAO type A inhibitors of reversible action (such as moclobemide). But, if the MAO type A inhibitor is administered after the cancellation of Anafranil, the duration of the break should be at least 2 weeks.
The combined use of anaphranil with selective serotonin reuptake inhibitors can lead to an increased effect on the serotonin system.
With the simultaneous use of anaphranil with selective serotonin reuptake inhibitors or serotonin and noradrenaline (norepinephrine) reuptake inhibitors, tricyclic antidepressants and lithium preparations, development of a serotonin syndrome with symptoms such as fever, myoclonus, agitation, convulsions, delirium and coma is possible.
If it is necessary to administer fluoxetine, it is recommended to take a two-three-week break between the use of anaphranil and fluoxetine - to stop the use of fluoxetine 2-3 weeks prior to the initiation of therapy with anaphranil or to prescribe fluoxetine 2-3 weeks after the end of treatment with anaphranil.
Anafranil can enhance the effect on the cardiovascular system of sympathomimetic drugs (adrenaline, norepinephrine, isoprenaline, ephedrine and phenylephrine), including. and when these substances are part of local anesthetics.
Pharmacokinetic interaction
The active substance of the drug Anafranil - clomipramine - is mostly excreted as metabolites. The main pathway of metabolism is demethylation to the active metabolite of N-desmethylclimipramine followed by hydroxylation and conjugation of N-desmethylclomipramine with clomipramine. Several isoenzymes of cytochrome P450, mainly CYP3A4, CYP2C19 and CYP1A2, participate in demethylation. Elimination of both active components is carried out by hydroxylation, which is catalyzed by CYP2D6.
Co-administration with inhibitors of the isoenzyme CYP2D6 can lead to an increase in the concentrations of both active components to threefold in persons with the phenotype of the rapid metabolizer of debrisoquine / sparteine. At the same time, in these patients the metabolism decreases to a level characteristic for persons with the phenotype of a weak metabolizer.
It is assumed that joint administration with inhibitors of isoenzymes CYP1A2, CYP2C19 and CYP3A4 can lead to an increase in clomipramine concentration and a decrease in the concentration of N-desmethylclimipramine.
- MAO inhibitors (eg, moclobemide) are contraindicated in the administration of clomipamine; in vivo they are potent inhibitors of CYP2D6.
- Antiarrhythmic drugs (for example, quinidine and propafenone) should not be used in conjunction with tricyclic antidepressants, t. they are potent inhibitors of CYP2D6.
- Selective serotonin reuptake inhibitors (such as fluoxetine, paroxetine or sertraline) inhibit CYP2D6; other drugs of this group (eg fluvoxamine) also inhibit CYP1A2, CYP2C19, which may lead to an increase in clomipramine concentration in the plasma and the development of corresponding undesirable effects. A 4-fold increase in the equilibrium concentration of clomipramine was observed with co-administration with fluvoxamine (the concentration of N-desmethylclomipramine decreased 2-fold).
- Joint use of neuroleptics (for example, phenothiazines) can lead to an increase in plasma concentrations of tricyclic antidepressants, a decrease in convulsive threshold and the occurrence of seizures. Combination with thioridazine can lead to the development of severe cardiac rhythm disturbances.
- Co-administration with cymetidine blocker of histamine H2 receptors (which is an inhibitor of some cytochrome P450 isoenzymes, including CYP2D6 and CYP3A4) can lead to an increase in plasma tricyclic antidepressant concentrations, which requires a reduction in the dose of the latter.
- There is no evidence to support the interaction between anaphranil (25 mg / day) and oral contraceptives (15 or 30 mg ethinylestradiol / day) with constant intake of the latter. There is no evidence that estrogens are inhibitors of CYP2D6, the main isoenzyme involved in eliminating clomipramine, so there is no reason to expect their interaction. Although simultaneous use of the tricyclic antidepressant imipramine and estrogens in high doses (50 mg / day), in some cases, the aggravation of side effects and the increased therapeutic effect of the antidepressant have been reported. It is not known whether these data are significant for the simultaneous use of clomipramine and estrogens in low doses. When combined use of tricyclic antidepressants and estrogens in high doses (50 mg / day), it is recommended to monitor the therapeutic effect of antidepressants and, if necessary, correct the dosage regimen.
- Methylphenidate may help increase the concentration of tricyclic antidepressants, possibly by suppressing their metabolism. With the joint use of these drugs, an increase in the concentration of tricyclic antidepressants in blood plasma is possible, and a dose reduction of the latter may be required.
- Some tricyclic antidepressants may enhance the anticoagulant effect of coumarins (eg, warfarin), possibly by inhibiting their metabolism (CYP2C9). There is no evidence to prove the ability of clomipramine to inhibit the metabolism of anticoagulants (warfarin). Nevertheless, when using this class of drugs, it is recommended to monitor the concentration of prothrombin in the plasma.
Joint reception of anaphranil with drugs - inducers of cytochrome P450, especially CYP3A4, CYP2C19 and / or CYP1A2 can lead to increased metabolism and reduce the efficacy of Anafranil.
Joint intake of anaphranil with CYP3A and CYP2C inducers, such as rifampicin or anticonvulsants (eg barbiturates, carbamazepine, phenobarbital and phenytoin), can lead to a decrease in clomipramine concentration in the plasma.
- Known inductors CYP1A2 (eg nicotine / other components of cigarette smoke) reduce the concentration of tricyclic antidepressants in blood plasma. The equilibrium concentration of clomipramine in cigarette smoking people is 2 times lower than that of non-smokers (the concentration of N-desmethylclomipramine did not change).
- Clomipramine, both in vivo and in vitro, inhibits the activity of CYP2D6 (oxidation of sparteine). Thus, clomipramine can increase concentrations of concomitantly used drugs metabolized mainly with the participation of CYP2D6 in individuals with the phenotype of a strong metabolizer.
