ANAFRANIL
Interaction
Pharmacodynamic type of interaction
Blockers of adrenergic neuronal transmission.
Anafranil can reduce or completely eliminate the antihypertensive effect of guanethidine, betanidine, reserpine, clonidine and alphamethyldopa. Therefore, in cases where treatment of arterial hypertension is required simultaneously with taking Anafranil, drugs of other classes (for example, vasodilators or beta-blockers) should be used.
Anticholinergics. Tricyclic antidepressants may potentiate the effect of anticholinergics (eg, phenothiazines, antiparkinsonian drugs, atropine, biperiden, antihistamines) on the eye, central nervous system, intestines and bladder.
CNS depressants. Tricyclic antidepressants may enhance the effects of alcohol and other drugs that have a depressant effect on the central nervous system (for example, barbiturates, benzodiazepines or anesthetics).
MAO inhibitors. Anafranil should not be prescribed for at least 2 weeks after discontinuation of MAO inhibitors due to the risk of developing severe symptoms and conditions such as hypertensive crisis, fever, as well as symptoms of serotonin syndrome: myoclonus, agitation, convulsions, delirium and coma. The same rule should be followed if a MAO inhibitor is prescribed after previous treatment with Anafranil. In any of these cases, the initial doses of Anafranil or MAO inhibitors should be low and should be increased gradually, under constant monitoring of the effects of the drug.
Current experience shows that Anafranil can be prescribed no earlier than 24 hours after discontinuation of reverse-acting MAO-A inhibitors, such as moclobemide. But, if a reversible MAO-A inhibitor is prescribed after Anafranil is discontinued, the duration of the break should be at least 2 weeks.
Selective serotonin reuptake inhibitors.
The combined use of Anafranil with these drugs can lead to an increased effect on the serotonin system.
Serotonergic agents. With simultaneous use of Anafranil with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants and lithium preparations, the development of serotonin syndrome with symptoms such as fever, myoclonus, agitation, convulsions, delirium and coma is possible. If it is necessary to prescribe fluoxetine, it is recommended to take a two to three week break between the use of Anafranil and fluoxetine - stop using fluoxetine 2-3 weeks before starting Anafranil therapy or prescribe fluoxetine 2-3 weeks after finishing Anafranil treatment.
Sympathomimetic agents.
Anafranil can enhance the effect on the cardiovascular system of adrenaline, norepinephrine, isoprenaline, ephedrine and phenylephrine (including when these substances are part of local anesthetics). Pharmacokinetic type of interaction
The active substance of Anafranil, clomipramine, is mainly excreted in the form of metabolites. The main route of metabolism is demethylation to the active metabolite N-desmethylclomipramine, followed by hydroxylation and conjugation of N-desmethylclomipramine with clomipramine. Several isoforms of cytochrome P450 are involved in demethylation, mainly CYP3A4, CYP2C19 and CYP1A2. Elimination of both active components occurs through hydroxylation, which is catalyzed by CYP2D6. Co-administration with inhibitors of the CYP2D6 isoform can lead to an increase in the concentrations of both active components by up to three times in individuals with the phenotype of a rapid metabolizer of debrisoquine/sparteine. At the same time, in these patients, metabolism decreases to a level characteristic of individuals with a poor metabolizer phenotype. It is assumed that co-administration with inhibitors of the CYP1A2, CYP2C19 and CYP3A4 isoforms may lead to an increase in the concentration of clomipramine and a decrease in the concentration of N-desmethylclomipramine.
MAO inhibitors (eg moclobemide) are contraindicated when taking clomipamine, as in vivo they are strong inhibitors of CYP2D6.
Antiarrhythmic drugs (eg quinidine and propafenone) should not be used in conjunction with tricyclic antidepressants, as they are strong inhibitors of CYP2D6.
Selective serotonin reuptake inhibitors (such as fluoxetine, paroxetine or sertraline) inhibit CYP2D6; other drugs in this group (for example, fluvoxamine) also inhibit CYP1A2, CYP2C19, which can lead to an increase in clomipramine plasma concentrations and the development of corresponding undesirable effects. A 4-fold increase in the equilibrium concentration of clomipramine was observed when taken together with fluvoxamine (the concentration of N-desmethylclomipramine decreased by 2 times).
- Concomitant use of antipsychotics (eg phenothiazines) may lead to increased plasma concentrations of tricyclic antidepressants, a decrease in the seizure threshold and the occurrence of seizures. Combination with thioridazine can lead to the development of severe heart rhythm disturbances.
- Combined use with the histamine (H2) receptor blocker cimetidine (which is an inhibitor of some isoforms of cytochrome P450, including CYP2D6 and CYP3A4) may lead to an increase in plasma concentrations of tricyclic antidepressants, which requires a reduction in the dose of the latter.
— There is no data confirming the interaction between Anafranil (at a dose of 25 mg per day) and oral contraceptives (15 or 30 mcg ethinyl estradiol per day) when taken continuously. There is no evidence that estrogens are inhibitors of CYP2D6, the main enzyme involved in the elimination of clomipramine, so there is no reason to expect their interaction.
Although, with the simultaneous use of the tricyclic antidepressant imipramine and estrogens in high doses (50 mcg per day), in some cases, worsening side effects and an increase in the therapeutic effect of the antidepressant have been reported. It is unknown whether these data are significant with respect to the concomitant use of clomipramine and low-dose estrogens. When tricyclic antidepressants and estrogens are used together in high doses (50 mcg per day), it is recommended to monitor the therapeutic effect of antidepressants and, if necessary, adjust the dosage regimen.
Methylphenidate (Ritalin) may increase concentrations of tricyclic antidepressants, possibly by inhibiting their metabolism. When using these drugs together, it is possible to increase the concentration of tricyclic antidepressants in the blood plasma, and it may be necessary to reduce the dose of the latter.
Some tricyclic antidepressants may enhance the anticoagulant effects of coumarins (eg, warfarin), possibly by inhibiting their metabolism (CYP2C9). There is no data demonstrating the ability of clomipromine to inhibit the metabolism of anticoagulants (warfarin). However, monitoring of plasma prothrombin concentrations is recommended when using this class of drugs.
Co-administration of Anafranil with drugs that induce cytochrome P450, especially CYP3A4, CYP2C19 and/or CYP1A2, can lead to increased metabolism and reduce the effectiveness of Anafranil.
Co-administration of Anafranil with drugs that induce CYP3A and CYP2C, such as rifampicin or anticonvulsants (for example, barbiturates, carbamazepine, phenobarbital and phenytoin), may lead to a decrease in plasma concentrations of clomipramine.
Known inducers of CYP1A2 (eg, nicotine and other components of cigarette smoke) reduce plasma concentrations of tricyclic antidepressants.
The steady-state concentration of clomipramine in cigarette smokers is 2 times lower than that in non-smokers (the concentration of N-desmethylclomipramine did not change). Clomipramine, both in vivo and in vitro (Ki=2.2 microM), inhibits the activity of CYP2D6 (sparteine oxidation). Therefore, clomipramine may increase concentrations of concomitantly administered drugs metabolized primarily by CYP2D6 in individuals with a strong metabolizer phenotype.
Pharmacodynamic type of interaction
Blockers of adrenergic neuronal transmission.
Anafranil can reduce or completely eliminate the antihypertensive effect of guanethidine, betanidine, reserpine, clonidine and alphamethyldopa. Therefore, in cases where treatment of arterial hypertension is required simultaneously with taking Anafranil, drugs of other classes (for example, vasodilators or beta-blockers) should be used.
Anticholinergics. Tricyclic antidepressants may potentiate the effect of anticholinergics (eg, phenothiazines, antiparkinsonian drugs, atropine, biperiden, antihistamines) on the eye, central nervous system, intestines and bladder.
CNS depressants. Tricyclic antidepressants may enhance the effects of alcohol and other drugs that have a depressant effect on the central nervous system (for example, barbiturates, benzodiazepines or anesthetics).
MAO inhibitors. Anafranil should not be prescribed for at least 2 weeks after discontinuation of MAO inhibitors due to the risk of developing severe symptoms and conditions such as hypertensive crisis, fever, as well as symptoms of serotonin syndrome: myoclonus, agitation, convulsions, delirium and coma. The same rule should be followed if a MAO inhibitor is prescribed after previous treatment with Anafranil. In any of these cases, the initial doses of Anafranil or MAO inhibitors should be low and should be increased gradually, under constant monitoring of the effects of the drug.
Current experience shows that Anafranil can be prescribed no earlier than 24 hours after discontinuation of reverse-acting MAO-A inhibitors, such as moclobemide. But, if a reversible MAO-A inhibitor is prescribed after Anafranil is discontinued, the duration of the break should be at least 2 weeks.
Selective serotonin reuptake inhibitors.
The combined use of Anafranil with these drugs can lead to an increased effect on the serotonin system.
Serotonergic agents. With simultaneous use of Anafranil with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants and lithium preparations, the development of serotonin syndrome with symptoms such as fever, myoclonus, agitation, convulsions, delirium and coma is possible. If it is necessary to prescribe fluoxetine, it is recommended to take a two to three week break between the use of Anafranil and fluoxetine - stop using fluoxetine 2-3 weeks before starting Anafranil therapy or prescribe fluoxetine 2-3 weeks after finishing Anafranil treatment.
Sympathomimetic agents.
Anafranil can enhance the effect on the cardiovascular system of adrenaline, norepinephrine, isoprenaline, ephedrine and phenylephrine (including when these substances are part of local anesthetics).
Pharmacokinetic type of interaction
The active substance of Anafranil, clomipramine, is mainly excreted in the form of metabolites. The main route of metabolism is demethylation to the active metabolite N-desmethylclomipramine, followed by hydroxylation and conjugation of N-desmethylclomipramine with clomipramine. Several isoforms of cytochrome P450 are involved in demethylation, mainly CYP3A4, CYP2C19 and CYP1A2. Elimination of both active components occurs through hydroxylation, which is catalyzed by CYP2D6. Co-administration with inhibitors of the CYP2D6 isoform may lead to increased
concentrations of both active components up to three times the value in individuals with the phenotype of a rapid metabolizer of debrisoquine/sparteine. At the same time, in these patients, metabolism decreases to a level characteristic of individuals with a poor metabolizer phenotype. It is assumed that co-administration with inhibitors of the CYP1A2, CYP2C19 and CYP3A4 isoforms may lead to an increase in the concentration of clomipramine and a decrease in the concentration of N-desmethylclomipramine.
MAO inhibitors (eg moclobemide) are contraindicated when taking clomipamine, as in vivo they are strong inhibitors of CYP2D6.
Antiarrhythmic drugs (eg quinidine and propafenone) should not be used in conjunction with tricyclic antidepressants, as they are strong inhibitors of CYP2D6.
Selective serotonin reuptake inhibitors (such as fluoxetine,
paroxetine or sertraline) inhibit CYP2D6, other drugs of this group
(for example, fluvoxamine) also inhibit CYP1A2, CYP2C19, which can lead to an increase in plasma concentrations of clomipramine and the development of related
unwanted effects. A 4-fold increase in equilibrium was observed
concentration of clomipramine when taken together with fluvoxamine (concentration
N-desmethylclomipramine decreased by 2 times).
- Concomitant use of antipsychotics (eg phenothiazines) may lead to increased plasma concentrations of tricyclic antidepressants, a decrease in the seizure threshold and the occurrence of seizures. Combination with thioridazine can lead to the development of severe heart rhythm disturbances.
- Combined use with the histamine (H2) receptor blocker cimetidine (which is an inhibitor of some isoforms of cytochrome P450, including CYP2D6 and CYP3A4) may lead to increased plasma concentrations
tricyclic antidepressants, which requires a reduction in the dose of the latter.
— There is no data confirming the interaction between Anafranil (at a dose of 25 mg per day) and oral contraceptives (15 or 30 mcg ethinyl estradiol per day) when taken continuously. There is no evidence that estrogens are inhibitors of CYP2D6, the main enzyme involved in the elimination of clomipramine, so there is no reason to expect their interaction.
Although, with the simultaneous use of the tricyclic antidepressant imipramine and estrogens in high doses (50 mcg per day), in some cases aggravation of side effects and increased therapeutic effect have been reported
antidepressant. It is unknown whether these data are significant in relation to
simultaneous use of clomipramine and estrogens in low doses. At
combined use of tricyclic antidepressants and estrogens in high
doses (50 mcg per day), monitoring of therapeutic effect is recommended
antidepressants, and, if necessary, adjustment of the dosage regimen.
Methylphenidate (Ritalin) may increase concentrations
tricyclic antidepressants, possibly due to suppression of their metabolism. At
combined use of these drugs may increase the concentration
tricyclic antidepressants in blood plasma, which may require
reducing the dose of the latter.
Some tricyclic antidepressants may enhance anticoagulation
action of coumarins (eg warfarin), possibly by inhibiting them
metabolism (CYP2C9). There is no data to demonstrate the ability of clomipromine
inhibit the metabolism of anticoagulants (warfarin). However, when
Monitoring is recommended when using this class of drugs
plasma prothrombin concentrations.
Co-administration of Anafranil with drugs that induce cytochrome P450, especially CYP3A4, CYP2C19 and/or CYP1A2, can lead to increased metabolism and reduce the effectiveness of Anafranil.
Co-administration of Anafranil with drugs that induce CYP3A and CYP2C, such as rifampicin or anticonvulsants (for example
barbiturates, carbamazepine, phenobarbital and phenytoin) may lead to decreased
clomipramine plasma concentrations.
Known inducers of CYP1A2 (for example, nicotine and other components of cigarette
smoke) reduce the concentrations of tricyclic antidepressants in the blood plasma.
The equilibrium concentration of clomipramine in cigarette smokers is 2 times lower than that
in non-smokers (the concentration of N-desmethylclomipramine did not change).
Clomipramine, both in vivo and in vitro (Ki=2.2 microM), inhibits the activity of CYP2D6 (sparteine oxidation). Therefore, clomipramine may increase concentrations of concomitantly administered drugs metabolized primarily by CYP2D6 in individuals with a strong metabolizer phenotype.
