Interactions : אינטראקציות

4.5    Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.
Cardiovascular effects

HALDOL is contraindicated in combination with medicinal products known to prolong the QTc interval (see section 4.3). Examples include:

•      Class IA antiarrhythmics (e.g. disopyramide, quinidine).
•      Class III antiarrhythmics (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol).
•      Certain antidepressants (e.g. citalopram, escitalopram).
•      Certain antibiotics (e.g. azithromycin, clarithromycin, erythromycin, levofloxacin, moxifloxacin, telithromycin).
•      Other antipsychotics (e.g. phenothiazine derivatives, sertindole, pimozide, ziprasidone)
•      Certain antifungals (e.g. pentamidine).
•      Certain antimalarials (e.g. halofantrine).
•      Certain gastrointestinal medicinal products (e.g. dolasetron).
•      Certain medicinal products used in cancer (e.g. toremifene, vandetanib).
•      Certain other medicinal products (e.g. bepridil, methadone).

This list is not exhaustive.

Caution is advised when HALDOL is used in combination with medicinal products known to cause electrolyte imbalance (see section 4.4).

Medicinal products that may increase haloperidol plasma concentrations 
Haloperidol is metabolised by several routes (see section 5.2). The major pathways are glucuronidation and ketone reduction. The cytochrome P450 enzyme system is also involved, particularly CYP3A4 and, to a lesser extent, CYP2D6. Inhibition of these routes of metabolism by another medicinal product or a decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations. The effect of CYP3A4 inhibition and of decreased CYP2D6 enzyme activity may be additive (see section 5.2). Based on limited and sometimes conflicting information, the potential increase in haloperidol plasma concentrations when a CYP3A4 and/or CYP2D6 inhibitor is coadministered may range between 20 to 40%, although in some cases, increases of up to 100% have been reported. Examples of medicinal products that may increase haloperidol plasma concentrations (based on clinical experience or drug interaction mechanism) include: 
•      CYP3A4 inhibitors – alprazolam, fluvoxamine, indinavir, itraconazole, ketoconazole, nefazodone, posaconazole, saquinavir, verapamil, voriconazole.
•      CYP2D6 inhibitors – bupropion, chlorpromazine, duloxetine, paroxetine, promethazine, sertraline, venlafaxine.
•      Combined CYP3A4 and CYP2D6 inhibitors: fluoxetine, ritonavir.
•      Uncertain mechanism – buspirone.

This list is not exhaustive.

Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTc-prolongation (see section 4.4). Increases in QTc have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day).

It is recommended that patients who take haloperidol concomitantly with such medicinal products be monitored for signs or symptoms of increased or prolonged pharmacologic effects of haloperidol, and the HALDOL dose be decreased as deemed necessary.

Medicinal products that may decrease haloperidol plasma concentrations 
Coadministration of haloperidol with potent enzyme inducers of CYP3A4 may gradually decrease the plasma concentrations of haloperidol to such an extent that efficacy may be reduced. Examples include:

•      Carbamazepine, phenobarbital, phenytoin, rifampicin, St John’s Wort (Hypericum, perforatum).

This list is not exhaustive.

Enzyme induction may be observed after a few days of treatment. Maximal enzyme induction is generally seen in about 2 weeks and may then be sustained for the same period of time after the cessation of therapy with the medicinal product. During combination treatment with inducers of CYP3A4, it is recommended that patients be monitored and the HALDOL dose increased as deemed necessary. After withdrawal of the CYP3A4 inducer, the concentration of haloperidol may gradually increase and therefore it may be necessary to reduce the HALDOL dose.

Sodium valproate is known to inhibit glucuronidation, but does not affect haloperidol plasma concentrations.

Effect of haloperidol on other medicinal products

Haloperidol can increase the CNS depression produced by alcohol or CNS-depressant medicinal products, including hypnotics, sedatives or strong analgesics. An enhanced CNS effect, when combined with methyldopa, has also been reported.

Haloperidol may antagonise the action of adrenaline and other sympathomimetic medicinal products (e.g. stimulants like amphetamines) and reverse the blood pressure-lowering effects of adrenergic-blocking medicinal products such as guanethidine.

Haloperidol may antagonise the effect of levodopa and other dopamine agonists.

Haloperidol is an inhibitor of CYP2D6. Haloperidol inhibits the metabolism of tricyclic antidepressants (e.g. imipramine, desipramine), thereby increasing plasma concentrations of these medicinal products.

Other forms of interaction

In rare cases the following symptoms were reported during the concomitant use of lithium and haloperidol: encephalopathy, extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, acute brain syndrome and coma. Most of these symptoms were reversible. It remains unclear whether this represents a distinct clinical entity.

Nonetheless, it is advised that in patients who are treated concomitantly with lithium and HALDOL, therapy must be stopped immediately if such symptoms occur.

Antagonism of the effect of the anticoagulant phenindione has been reported.