Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Interactions resulting in a contraindication
MAO inhibitors
If clomipramine should be administered after treatment with MAO inhibitors, a washout period of at least 21 days is advised (there is a risk of severe symptoms such as hypertensive crisis, hyperpyrexia and those consistent with serotonin syndrome, e.g. myoclonus, agitation seizures, delirium and coma). The same applies when giving a MAO inhibitor after previous treatment with clomipramine. In both cases Anafranil or the MAO inhibitor should initially be given in small, gradually increasing doses and its effects monitored until the patient has reached the optimal dosage (see section 4.3).
There is evidence to suggest that Anafranil may be given as little as 24 hours after a reversible MAO-A inhibitor such as moclobemide, but the 21 days washout period must be observed if the MAO-A inhibitor is given after Anafranil has been used. MAO inhibitors such as moclobemide, are not suitable for concomitant treatment with Anafranil as CYP2D6 inhibitors (see section 4.3).

Interactions resulting in a concomitant use not recommended

Antiarrhythmics (such as quinidine and propafenone) which are potent inhibitors of CYP2D6 should not be used in combination with tricyclic antidepressants.

Diuretics
Diuretics may lead to hypokalaemia, which in turn increases the risk of QTc prolongation and torsades de pointes. Hypokalaemia should therefore be treated prior to administration of Anafranil (see sections 4.2 and 4.4).

Selective serotonin reuptake inhibitors (SSRIs)
SSRIs are strong inhibitors of CYP2D6 (such as fluoxetine, paroxetine, or sertraline), CYP1A2 and CYP2C19 (e.g., fluvoxamine) and may increase plasma concentrations of clomipramine, with corresponding adverse effects. Steady-state serum levels of clomipramine increased ~4-fold by co-administration of fluvoxamine (N- desmethylclomipramine decreased ~2-fold) (see sections 4.2 and 4.4).
Comedication with SSRIs may lead to additive effects on the serotonergic system.

Serotonergic Agents
The risk of serotonin syndrome, a potentially life-threatening condition, is increased when clomipramine is administered with serotonergic co-medications such as selective serotonin re-uptake inhibitors (SSRIs), serotonin and noradrenergic reuptake inhibitors serotonin norepinephrine re-uptake inhibitors (SNRIs), tricyclic antidepressants, buprenorphine or lithium (see sections 4.2 and 4.4). A washout period of two to three weeks is advised before and after treatment with fluoxetine.

Interactions to be considered

Interactions resulting in increased effect of Anafranil
Concomitant administration of CYP2D6 inhibitors may lead to an increase in concentration of both active components, up to ~3-fold in patients with a debrisoquine/sparteine extensive metabolizer phenotype, converting them to a poor-metabolizer phenotype. Concomitant administration of CYP1A2, CYP2C19 and CYP3A4 inhibitors are expected to increase clomipramine concentrations and decrease N- desmethylclomipramine, thus not necessarily affecting the overall pharmacology.

Terbinafine
Oral antifungal terbinafine. Co-administration of Anafranil with terbinafine, a strong inhibitor of CYP2D6, may result in increased exposure and accumulation of clomipramine and its N-demethylated metabolite.
Therefore, dose adjustments of Anafranil may be necessary when co-administered with terbinafine.

Cimetidine
Co-administration with the histamine2 (H2)-receptor antagonist cimetidine (an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4) may increase plasma concentrations of tricyclic antidepressants, whose dosage should therefore be reduced.

Oral contraceptives
No interaction between long-term oral contraceptive use (15 or 30 micrograms ethinyl estradiol daily) and Anafranil (25 mg daily) has been documented. Estrogens are not known to be inhibitors of CYP2D6, the major enzyme involved in clomipramine clearance and, therefore, no interaction is expected. Although, in a few cases with high dose estrogen (50 micrograms daily) and the tricyclic antidepressant imipramine, increased side effects and therapeutic response were noted, it is unclear as to the relevance of these cases to clomipramine and lower dose estrogen regimens. Monitoring therapeutic response of tricyclic antidepressants at high dose estrogen regimens (50 micrograms daily) is recommended and dose adjustments may be necessary.

Antipsychotics
Comedication of antipsychotics (e.g., phenothiazines) may result in increased plasma levels of tricyclic antidepressants, a lowered convulsion threshold, and seizures. Combination with thioridazine may produce severe cardiac arrhythmias.

Methylphenidate
Methylphenidate, such as ritaline, may increase concentrations of tricyclic antidepressants by potentially inhibiting their metabolism and a dose reduction of the tricyclic antidepressant may be necessary.

Valproate
Concomitant administration of valproate with clomipramine may cause inhibition of CYP2C and/or UGT enzymes resulting in increased serum levels of clomipramine and desmethylclomipramine.

Grapefruit, grapefruit juice, or cranberry juice
Concomitant administration of Anafranil with grapefruit, grapefruit juice, or cranberry juice may increase the plasma concentrations of clomipramine.

Interactions resulting in decreased effect of Anafranil

Rifampicin
Rifampicin (CYP3A and CYP2C inducer) may decrease clomipramine concentrations as concomitant administration of drugs known to induce cytochrome P450 enzymes, particularly CYP3A4, CYP2C19, may accelerate the metabolism and decrease the efficacy of Anafranil.

Anticonvulsants
Anticonvulsants (CYP3A and CYP2C inducer) (e.g., barbiturates, carbamazepine, phenobarbital, and phenytoin), may decrease clomipramine concentrations as concomitant administration of drugs known to induce cytochrome P450 enzymes, particularly CYP3A4, CYP2C19, may accelerate the metabolism and decrease the efficacy of Anafranil.

Cigarette smoking
Known inducers of CYP1A2 (e.g., nicotine/components in cigarette smoke), decrease plasma concentrations of tricyclic drugs. In cigarette smokers, clomipramine steady-state plasma concentrations were decreased 2- fold compared to non-smokers (no change in N-desmethylclomipramine).

Colestipol and cholestyramine
Concomitant administration of ion exchange resins such as cholestyramine or colestipol may reduce the plasma levels of clomipramine. Staggering the dosage of clomipramine and resins, such that the drug is administered at least 2 h before or 4-6 h after the administration of resins, is recommended.

St. John’s wort
Concomitant administration of Anafranil with St. John’s wort during the treatment may decrease the plasma concentrations of clomipramine.
Interactions affecting other drugs

Anticholinergic agents
Tricyclic antidepressants may potentiate the effects of these drugs (e.g., phenothiazine, antiparkinsonian agents, antihistamines, atropine, biperiden) on the eye, central nervous system, bowel and bladder.
Antiadrenergic agents
Tricyclic antidepressants may diminish or abolish the antihypertensive effects of clonidine, guanethidine, betanidine, reserpine, and alpha-methyldopa. If necessary, antihypertensives of a different type should be given (e.g., vasodilators, or beta- blockers).

CNS depressants
Tricyclic antidepressants may potentiate the effects of alcohol and other central depressant substances (e.g., barbiturates, benzodiazepines, or general anaesthetics).

Sympathomimetic drugs
Tricyclic antidepressants may potentiate the cardiovascular effects of sympathomimetic drugs, such as adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine (e.g., local anaesthetics containing sympathomimetic drugs).

Anticoagulants
Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin drugs, such as warfarin, and this may be through inhibition of their metabolism (CYP2C9). There is no evidence for the ability of clomipramine to inhibit the metabolism of anticoagulants, such as warfarin, however, careful monitoring of blood coagulation has been advised for this class of drug.
Clomipramine is also an in vitro (Ki = 2.2 microM) and in vivo inhibitor of CYP2D6 activity (sparteine oxidation) and therefore, may cause increased plasma concentrations of co-administered compounds that are primarily cleared by CYP2D6 in extensive metabolisers.