Haloperidol

Pharmacological properties

mechanism of action. haloperidol decanoate is an ester of haloperidol and decanoic acid, a long-acting antipsychotic drug that belongs to butyrophenone derivatives. after injection of haloperidol, decanoate is gradually released from muscle tissue and slowly hydrolysed, turning into free haloperidol, which enters the systemic circulation.

Haloperidol is a potent central antagonist of type 2 dopamine receptors; at recommended doses it has low α₁-antiadrenergic activity and does not have antihistamine or anticholinergic action.

Pharmacodynamic effects. Haloperidol suppresses delusions and hallucinations as a result of blockade of dopaminergic signaling pathways in mesolimbic structures. The central antidopaminergic effect is manifested in the basal ganglia (nigrostriatal nodes). Haloperidol effectively eliminates psychomotor agitation, which explains its beneficial effect in mania and other syndromes accompanied by agitation.

The effect on the basal ganglia probably underlies the unwanted extrapyramidal movement disorders (dystonia, akathisia, parkinsonism).

The antidopaminergic effect of haloperidol on lactotrophic cells of the anterior pituitary gland causes hyperprolactinemia, which occurs due to the elimination of tonic inhibition of dopamine-mediated prolactin secretion.

Clinical researches. In clinical trials, patients were reported to be treated with oral haloperidol before switching to haloperidol decanoate. Sometimes patients previously received another oral antipsychotic drug.

Pharmacokinetics

Absorption. After injection of haloperidol decanoate, a slow and constant release of free haloperidol from the depot occurs. The concentration of haloperidol in blood plasma rises gradually, reaching a maximum, usually 3–9 days after injection.

With regular monthly administration, the saturation stage in blood plasma is reached after 2–4 months.

Distribution. Binding to plasma proteins in adult patients averages about 88–92%. The degree of binding to blood plasma proteins is characterized by high intersubject variability. Haloperidol is rapidly distributed in various tissues and organs, as evidenced by the large volume of distribution (average value of 8–21 l / kg after iv administration). Haloperidol easily penetrates the BBB. It also crosses the placenta and is detected in breast milk.

Biotransformation. Haloperidol undergoes active metabolism in the liver. The main pathways of haloperidol metabolism in the human body are glucuronidation, reduction to ketones, oxidative N-dealkylation and the formation of pyridinium metabolites. It is believed that the metabolites of haloperidol do not significantly affect its activity, but about 23% of the drug is metabolized by recovery, and the reverse transition of the restored haloperidol metabolite to haloperidol cannot be completely excluded. In the metabolism of haloperidol, cytochrome P450 isoenzymes CYP 3A4 and CYP 2D6 are involved. Inhibition or induction of the CYP 3A4 enzyme or inhibition of the CYP 2D6 enzyme may affect haloperidol metabolism. A decrease in the activity of the CYP 2D6 enzyme can lead to an increase in haloperidol concentration.

Final t_½ haloperidol after administration of haloperidol decanoate averages 3 weeks. This is more than with other dosage forms, where T_½ haloperidol averages 24 hours after administration and 21 hours after administration.

The imaginary clearance of haloperidol after extravascular administration is 0.9–1.5 l / h / kg and decreases in slow CYP 2D6 metabolizers.The reduced activity of the CYP 2D6 enzyme can lead to an increase in haloperidol concentration. The intersubject variability (coefficient of variation,%) of haloperidol clearance in patients with schizophrenia was 44% in a population pharmacokinetic analysis. After administration of haloperidol, 21% of the dose is excreted in feces and 33% in urine. Less than 3% of the dose is excreted unchanged in the urine.

Linearity / nonlinearity. The pharmacokinetics of haloperidol after iv injection of haloperidol decanoate is dose-dependent. With the introduction of doses of 450 mg between the dose and the concentration of haloperidol in blood plasma, an almost linear relationship is observed.

Special patient groups

Elderly patients. The concentration of haloperidol in the blood plasma of elderly patients is higher than in adult patients of a young age when using the same dose. The results of small clinical studies indicate a lower clearance and a longer T_½ haloperidol in elderly patients. These results correspond to the range of observed fluctuations in the pharmacokinetic parameters of haloperidol. A dose adjustment of haloperidol is recommended for use in elderly patients (see APPLICATION).

Renal failure. The effect of renal failure on the pharmacokinetics of haloperidol has not been studied. About a third of the dose of haloperidol is excreted in the urine, mainly in the form of metabolites. Less than 3% of the dose is excreted unchanged in the urine.

Haloperidol metabolites do not significantly affect the activity of haloperidol, although it is impossible to completely exclude the reverse conversion of the reduced haloperidol metabolite to haloperidol. Despite the fact that impaired renal function should not affect the elimination of haloperidol to a clinically significant degree, caution is advised in the treatment of patients with impaired renal function, especially in cases of severe renal failure, due to prolonged T_½ haloperidol and its reduced metabolite and the possibility of accumulation (see APPLICATION).

Due to the large volume of distribution of haloperidol and its binding to plasma proteins using dialysis, a very small amount of the drug can be withdrawn.

Liver failure. The effect of liver failure on the pharmacokinetics of haloperidol has not been studied. However, impaired liver function can have a significant effect on the pharmacokinetics of haloperidol, because it is actively metabolized in the liver. For patients with impaired liver function, it is recommended to adjust the dose and take safety measures (see APPLICATION and SPECIAL INSTRUCTIONS).

The relationship of pharmacokinetics and pharmacodynamics

Therapeutic concentrations. According to published data from numerous clinical trials, the therapeutic effect in most patients with acute or chronic schizophrenia is achieved with a plasma concentration of 1-10 ng / ml. Some patients may require higher drug concentrations due to the high intersubjective variability of the pharmacokinetic parameters of haloperidol.

In patients with a first attack of schizophrenia who received haloperidol in short-acting dosage forms, a therapeutic response can be achieved at concentrations of at least 0.6–3.2 ng / ml. 60–80% D binding₂-receptors better ensures the achievement of a therapeutic response with minimal extrapyramidal symptoms. On average, haloperidol concentration in this range can be obtained using doses of 1–4 mg / day.

Due to the high intersubjective variability of the pharmacokinetic parameters of haloperidol and the dependence of the effect on concentration, it is recommended to select an individual dose of haloperidol decanoate based on the patients response to treatment.It is necessary to take into account the time after changing the dose to achieve a new stable plasma concentration of haloperidol and the additional time for the manifestation of a therapeutic response. In some cases, it may be appropriate to measure the concentration of haloperidol in the blood.

Cardiovascular effects. The risk of lengthening the Q – Tc interval increases with increasing dose and concentration of haloperidol in blood plasma.

Extrapyramidal symptoms. Extrapyramidal symptoms can develop with the use of the drug in the therapeutic dose range, although their frequency, as a rule, increases with the use in doses exceeding therapeutic.

Indications

Supportive care for schizophrenia and schizoaffective disorders in adult patients whose condition has stabilized while taking oral haloperidol.

Application

The start of treatment and dose titration should be closely monitored.

Dosage. An individual dose will depend on both the severity of the symptoms and the current dose of haloperidol. The lowest effective dose should always be used.

The initial dose of haloperidol decanoate is set based on a multiple increase in the daily dose of haloperidol; special recommendations for the transition from other antipsychotic drugs have not been developed (see PHARMACOLOGICAL PROPERTIES).

Adults (over 18 years old)

Table 1. Dosing recommendations for haloperidol decanoate for adult patients (from 18 years)

Transition from taking haloperidol Haloperidol decanoate is recommended in a 10-15-fold daily dose of haloperidol. The dose of haloperidol decanoate for most patients is 25-150 mg

Continued treatment It is recommended to increase the dose of haloperidol decanoate by 50 mg once every 4 weeks (depending on the individual patients response) until the optimal therapeutic effect is achieved. The most effective dose, as a rule, ranges from 50-200 mg. If it is necessary to administer doses of 200 mg once every 4 weeks, it is recommended to assess the individual ratio of benefit and risk. Do not exceed the maximum dose of 300 mg once every 4 weeks, since safety concerns outweigh the clinical benefits of treatment

Dosing interval Typically, the interval between injections is 4 weeks. Correction of the dosage interval may be required (depending on the individual response of the patient)

Additional use of haloperidol in another dosage form Additional treatment with haloperidol in a different dosage form may be required when switching to haloperidol decanoate treatment, for dose selection or during exacerbation of episodes of psychotic symptoms (depending on the individual patients response). The total total dose of haloperidol in two dosage forms should not exceed the corresponding maximum dose of oral haloperidol 20 mg / day

Special patient groups

Elderly patients

Table 2. Dosing recommendations for haloperidol decanoate for elderly patients

Transition from taking haloperidol Low doses of haloperidol decanoate 12.5–25 mg are recommended.

Continued treatment It is recommended only to adjust the dose of haloperidol decanoate, if necessary (in accordance with the individual response of the patient), until the optimal therapeutic effect is achieved. The most effective dose, as a rule, is 25–75 mg. Doses in excess of 75 mg once every 4 weeks can be prescribed only to patients who tolerated higher doses, and only after re-evaluating the individual ratio of benefit and risk to the patient

Dosing interval Typically, the interval between injections is 4 weeks. Correction of the dosage interval may be required (depending on the individual response of the patient)

Additional use of haloperidol in another dosage form Additional treatment with haloperidol in a different dosage form may be required when switching to haloperidol decanoate treatment, for dose selection or during exacerbation of episodes of psychotic symptoms (depending on the individual patients response). The total total dose of haloperidol in two dosage forms should not exceed the corresponding maximum dose of haloperidol 5 mg / day or the previously prescribed oral dose of haloperidol, which the patient received during long-term oral haloperidol therapy

Renal failure. The effect of renal failure on the pharmacokinetics of haloperidol has not been studied.

Dose adjustment is not recommended, but caution should be exercised in treating patients with renal failure. Patients with severe renal failure may require a lower initial dose, followed by increasing the dose in smaller steps and at longer intervals than in patients with normal renal function (see PHARMACOLOGICAL PROPERTIES).

Liver failure. The effect of liver failure on the pharmacokinetics of haloperidol has not been studied.

Since haloperidol undergoes active metabolism in the liver, it is recommended to reduce the initial dose by 2 times and increase it with smaller steps and at longer intervals than in patients with normal liver function (see SPECIAL INSTRUCTIONS and PHARMACOLOGICAL PROPERTIES).

Use in children. The safety and effectiveness of haloperidol decanoate in children and adolescents (under the age of 18 years) have not been established. No data available.

Mode of application. The drug is intended for i / m administration only! It is forbidden to enter in / in!

Haloperidol decanoate is used as a single intramuscular injection deep into the gluteal muscle. It is recommended to alternate gluteal