Haloperidol decanoate (Solution) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Contact Information

GEDEON RICHTER Plc. (Hungary)

ATC Code

N05AD01 (Haloperidol)

Active Substance

Haloperidol (Rec.INN registered by WHO)

Dosage Form

Haloperidol decanoate

Oil solution for intramuscular administration 50 mg/1 ml: amp. 5 pcs.

Dosage Form, Packaging, and Composition

Solution for intramuscular administration (oil-based) transparent, yellow or greenish-yellow in color.

Excipients: benzyl alcohol, sesame oil.

1 ml – dark glass ampoules (5) – plastic trays (1) – cardboard packs.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic agent (neuroleptic)

Pharmacological Action

Haloperidol decanoate is an ester of haloperidol and decanoic acid, it is a long-acting antipsychotic drug belonging to the butyrophenone derivatives. After intramuscular administration, haloperidol decanoate is gradually released from the muscle tissue and slowly hydrolyzed to form free haloperidol, which is absorbed into the systemic circulation. It is a potent antagonist of central dopamine D₂ receptors, at recommended doses it exhibits low alpha₁-adrenergic blocking activity, and does not possess antihistaminic or cholinergic blocking action.

Haloperidol suppresses delusions and hallucinations by blocking dopaminergic signaling pathways in the mesolimbic structures. The central antidopaminergic action is manifested in the basal ganglia (nigrostriatal fibers). Haloperidol effectively eliminates psychomotor agitation, which explains its beneficial effect in manias and other syndromes accompanied by agitation.

The effect on the basal ganglia probably underlies the undesirable extrapyramidal motor disorders (muscle dystonia, akathisia, and parkinsonism).

The antidopaminergic action of haloperidol on the lactotroph cells of the anterior pituitary gland causes hyperprolactinemia due to the removal of dopamine-mediated tonic inhibition of prolactin secretion.

Pharmacokinetics

Absorption

After intramuscular administration of haloperidol decanoate, a slow and constant release of free haloperidol from the depot occurs. Plasma concentration increases gradually, reaching a maximum, usually 3-9 days after the injection.

Steady-state plasma concentration of the drug in patients receiving monthly injections is achieved after 2-4 months.

Distribution

Plasma protein binding in adults averages from 88 to 92%. The degree of plasma protein binding is characterized by high interindividual variability. Haloperidol is rapidly distributed to various tissues and organs, as evidenced by a large V_d (on average from 8 to 21 L/kg after intravenous administration). Haloperidol easily crosses the blood-brain barrier. It also crosses the placental barrier and into breast milk.

Metabolism

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 formation of pyridinium derivatives. Haloperidol metabolites are not considered to contribute significantly to its activity; however, about 23% of the drug is biotransformed by reduction, and the reverse conversion of the reduced metabolite to the original compound cannot be completely ruled out. Haloperidol metabolism involves cytochrome P450 isoenzymes CYP3A4 and CYP2D6. Inhibition or induction of the CYP3A4 isoenzyme or inhibition of the CYP2D6 isoenzyme may affect the metabolism of haloperidol. Reduced activity of the CYP2D6 isoenzyme may lead to increased haloperidol concentrations.

Elimination

After intramuscular administration of haloperidol decanoate, the terminal T_1/2 averages 3 weeks. This is longer than with other dosage forms of haloperidol, for which the terminal T_1/2 averages 24 hours after oral administration and 21 hours after intramuscular administration. The apparent clearance of haloperidol after extravascular administration ranges from 0.9 to 1.5 L/h/kg and is reduced in slow metabolizers of the CYP2D6 isoenzyme. Reduced activity of the CYP2D6 isoenzyme may lead to increased haloperidol concentrations. Interindividual variability (coefficient of variation, %) of haloperidol clearance in patients with schizophrenia in a population pharmacokinetic analysis was 44%. After intravenous administration of haloperidol, 21% of the dose is excreted via the intestine, and 33% via the kidneys. Less than 3% of the drug dose is excreted unchanged by the kidneys.

Linearity

The pharmacokinetics of haloperidol after intramuscular administration of haloperidol decanoate are dose-dependent. When doses less than 450 mg are administered, there is an almost linear relationship between the dose and the plasma concentration of haloperidol.

Pharmacokinetics in special patient groups

Elderly patients (over 65 years). Plasma concentrations of haloperidol in elderly patients were higher than in younger patients when the same dose was administered. Results from small clinical studies indicate reduced clearance and a longer T_1/2 of haloperidol in elderly patients. The results fall within the range of observed fluctuations in haloperidol pharmacokinetic parameters. When used in elderly patients, dose adjustment is recommended (see section “Dosage Regimen”).

Patients with renal impairment. The effect of renal impairment on the pharmacokinetics of haloperidol has not been studied. Although impaired renal function should not have a clinically significant effect on the elimination of haloperidol, caution is recommended when treating patients with renal impairment, especially in cases of severe renal impairment, due to the prolonged T_1/2 of haloperidol and its reduced metabolite and the possibility of accumulation (see section “Dosage Regimen”).

Due to the large V_d of haloperidol and the high degree of plasma protein binding, dialysis can remove an extremely small amount of the drug.

Patients with hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of haloperidol has not been studied. However, hepatic impairment may have a significant effect on the pharmacokinetics of haloperidol, as it is actively metabolized in the liver. Consequently, it is recommended to reduce the initial dose by half and exercise caution when treating patients with hepatic impairment (see sections “Dosage Regimen” and “Special Instructions”).

Pharmacokinetic-pharmacodynamic relationship

Therapeutic concentrations. Based on published data from numerous clinical studies, the therapeutic effect in most patients with acute or chronic forms of schizophrenia is achieved at plasma drug concentrations from 1 to 10 ng/ml. Some patients may require higher concentrations due to high interindividual variability in haloperidol pharmacokinetic parameters.

In patients with a first episode of schizophrenia, a response to therapy may be achieved at concentrations from 0.6 to 3.2 ng/ml, as shown by the assessment of the proportion of occupied D₂ receptors, provided that 60-80% of occupied D₂ receptors best provide a therapeutic response to therapy with minimal extrapyramidal symptoms. On average, concentrations in this range can be achieved with daily doses from 1 to 4 mg. Due to the high interindividual variability in haloperidol pharmacokinetic parameters and the concentration-dependent effect, it is recommended to individualize the dose of haloperidol decanoate based on the patient’s response to treatment. The time after a dose change required to reach a new steady-state plasma concentration and the additional time for the therapeutic response to manifest must be taken into account. In individual cases, measurement of haloperidol blood concentration may be appropriate.

Effect on the cardiovascular system. The risk of QTc interval prolongation increases with increasing dose and plasma concentration of haloperidol.

Extrapyramidal symptoms. Extrapyramidal symptoms may develop when the drug is used within the therapeutic range, although their frequency generally increases when used in doses exceeding therapeutic ones.

Indications

• Haloperidol decanoate is used for maintenance therapy of schizophrenia and schizoaffective disorders in adult patients whose condition is stabilized on oral haloperidol.

ICD codes

Dosage Regimen

The drug Haloperidol decanoate is intended for intramuscular administration only and must not be administered intravenously. It is administered deep intramuscularly into the gluteal region. Alternating gluteal muscles is recommended. Administration of more than 3 ml of the drug is not recommended, as the patient may experience discomfort.

Initiation of treatment and dose selection should be carried out under careful medical supervision.

The individual dose depends on the severity of symptoms and the current dose of oral haloperidol. Patients should always receive the minimum effective dose. The initial dose of haloperidol decanoate is set based on a multiple of the daily dose of oral haloperidol; specific recommendations for switching from other antipsychotic drugs have not been developed.

Dosing recommendations for Haloperidol decanoate in adult patients

Special patient groups

Patients with renal impairment. The effect of renal impairment on the pharmacokinetics of haloperidol has not been studied. Dose adjustment is not recommended, but caution should be exercised when treating patients with renal impairment. However, patients with severe renal impairment may require a lower initial dose with subsequent dose increases in smaller increments and at longer intervals than patients with normal renal function (see section “Pharmacokinetics”).

Patients with hepatic impairment. The effect of hepatic impairment 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 half and increase it in smaller increments and at longer intervals than in patients with normal liver function (see sections “Special Instructions” and “Pharmacokinetics”).

Children and adolescents under 18 years. The use of Haloperidol decanoate in children and adolescents under 18 years of age is contraindicated, as there are no clinical trial data on the safety and efficacy of use in this patient group.

Elderly patients (over 65 years).

Dosing recommendations for Haloperidol decanoate in elderly patients

Adverse Reactions

The frequency of adverse reactions is based on research data and clinical experience in the post-registration period of haloperidol and is presented according to the following classification: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data). In each frequency category, adverse reactions are distributed by system-organ class.

Blood and lymphatic system disorders frequency unknown – pancytopenia, agranulocytosis, thrombocytopenia, leukopenia, neutropenia.

Immune system disorders frequency unknown – hypersensitivity reactions, anaphylactic reaction.

Endocrine disorders frequency unknown – hyperprolactinemia, inappropriate ADH secretion.

Metabolism and nutrition disorders frequency unknown – hypoglycemia.

Psychiatric disorders common – insomnia, depression; uncommon – psychotic disorder, agitation, confusional state, loss of libido, decreased libido, anxiety.

Nervous system disorders very common – extrapyramidal disorders; common – akathisia, parkinsonism, masked facies, tremor, somnolence, lethargy; uncommon – akinesia, dyskinesia, dystonia, cogwheel rigidity, hypertonia, headache; frequency unknown – neuroleptic malignant syndrome, tardive dyskinesia, seizures, bradykinesia, hyperkinesia, hypokinesia, dizziness, involuntary muscle contractions, impaired coordination, nystagmus.

Eye disorders: uncommon – oculogyric crisis, blurred vision, visual impairment.

Cardiac disorders uncommon – tachycardia; frequency unknown – ventricular fibrillation, torsades de pointes, ventricular tachycardia, extrasystoles.

Vascular disorders frequency unknown – arterial hypotension, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders frequency unknown – laryngeal edema, bronchospasm, laryngospasm, dyspnea.

Gastrointestinal disorders common – constipation, dry mouth, increased salivation; frequency unknown – vomiting, nausea.

Hepatobiliary disorders frequency unknown – acute hepatic failure, hepatitis, cholestasis, jaundice, abnormal liver function tests.

Skin and subcutaneous tissue disorders frequency unknown – angioedema, exfoliative dermatitis, leukocytoclastic vasculitis, photosensitivity reaction, urticaria, pruritus, rash, hyperhidrosis.

Musculoskeletal and connective tissue disorders common – muscle rigidity; frequency unknown – rhabdomyolysis, torticollis, trismus, muscle spasms, muscle twitching, musculoskeletal stiffness.

Renal and urinary disorders frequency unknown – urinary retention.

Pregnancy, puerperium and perinatal conditions frequency unknown – neonatal withdrawal syndrome.

Reproductive system and breast disorders common – sexual dysfunction; frequency unknown – priapism, amenorrhea, galactorrhea, dysmenorrhea, menorrhagia, erectile dysfunction, gynecomastia, breast pain, breast discomfort, menstrual disorder.

General disorders and administration site conditions common – injection site reactions; frequency unknown – sudden death, face edema, edema, hyperthermia, hypothermia, gait disturbance, injection site abscess.

Investigations common – weight increased; frequency unknown – electrocardiogram QT prolonged, weight decreased.

Class-specific effects of antipsychotic drugs when using antipsychotic drugs, cases of cardiac arrest, venous thromboembolism (VTE), including pulmonary embolism and deep vein thrombosis have also been reported. The frequency of these adverse reactions is not established.

Contraindications

• Hypersensitivity to haloperidol and/or other butyrophenone derivatives or to any of the excipients;
• Coma;
• CNS depression
• Parkinson’s disease;
• Dementia with Lewy bodies;
• Progressive supranuclear palsy;
• Congenital long QT syndrome or a history of QT interval prolongation;
• Recent acute myocardial infarction;
• Decompensated heart failure;
• History of ventricular arrhythmia or polymorphic ventricular tachycardia of the ‘torsades de pointes’ type;
• Uncompensated hypokalemia;
• Concomitant use of drugs that cause QT interval prolongation (see section “Drug Interactions”);
• Children and adolescents under 18 years of age (due to the lack of clinical trial data).

With caution

Decompensated cardiovascular diseases (including angina pectoris, intracardiac conduction disorders), epilepsy, hepatic and/or renal failure, hyperthyroidism (with manifestations of thyrotoxicosis), cardiopulmonary and respiratory failure (including in COPD and acute infectious diseases), prostatic hyperplasia with urinary retention, alcoholism, depression, old age.

Use in Pregnancy and Lactation

Pregnancy

Data on the use in a small number of pregnant women (more than 400 pregnancies with known outcome) do not confirm the presence of teratogenic effects, fetotoxicity or neonatal toxicity of haloperidol. Nevertheless, isolated cases of congenital developmental defects have been described against the background of haloperidol use in combination with other drugs during pregnancy. Animal studies have established toxic effects on reproductive function. As a precautionary measure, the use of Haloperidol decanoate during pregnancy should be avoided.

In newborns exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy, there is a risk of developing adverse reactions, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration after delivery. They exhibited agitation, hypertonia, hypotonia, tremor, drowsiness, respiratory distress and feeding disorders. Consequently, careful monitoring of newborns is recommended.

Breastfeeding period

Haloperidol passes into breast milk. Haloperidol is detected in small amounts in the plasma and urine of newborns who received breast milk from mothers taking Haloperidol. Information on the effect of haloperidol on breastfed infants is insufficient. The decision to discontinue breastfeeding or discontinue therapy with Haloperidol decanoate should be made taking into account the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Fertility

Haloperidol increases prolactin concentration. Hyperprolactinemia may suppress the synthesis of gonadotropin-releasing hormone (GnRH) in the hypothalamus, leading to reduced secretion of gonadotropins in the pituitary gland. This causes impaired reproductive function due to inhibition of sex hormone synthesis in men and women.

Use in Hepatic Impairment

The drug should be prescribed with caution to patients with hepatic insufficiency.

Use in Renal Impairment

The drug should be prescribed with caution to patients with renal insufficiency.

Pediatric Use

The drug is contraindicated in children.

Geriatric Use

A lower initial dose is recommended for elderly patients. Subsequently, depending on the effect, the dose may be increased.

Special Precautions

Increased mortality in elderly patients with dementia

Rare cases of sudden death have been reported in patients with mental disorders taking antipsychotic drugs, including Haloperidol (see section “Adverse Reactions”).

Elderly patients with dementia-related psychosis treated with antipsychotic drugs have an increased risk of death. An analysis of seventeen placebo-controlled studies (analysis of the first 10 weeks of therapy), mainly involving patients taking atypical antipsychotic drugs, showed that the risk of death in treated patients was 1.6-1.7 times higher than the risk of death in patients taking placebo. In a 10-week controlled study, mortality in patients receiving antipsychotic drugs was about 4.5% compared to 2.6% in the placebo group. Although the causes of death varied, most deaths were of cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) nature. Observational studies suggest that the use of haloperidol in elderly patients is also associated with increased mortality. This association may be more pronounced with the use of haloperidol than with atypical antipsychotics, is most evident within the first 30 days after starting treatment, and persists for at least 6 months. The extent to which this association is due to the drug versus underlying patient comorbidities and other characteristics has not yet been established.

Haloperidol decanoate is not intended for the treatment of behavioral disorders associated with dementia.

Effect on the cardiovascular system

In addition to sudden death, QT interval prolongation and/or ventricular arrhythmias have been reported with the use of haloperidol (see sections “Contraindications” and “Adverse Reactions”). The risk of these phenomena increases with the use of high doses of the drug, with high plasma concentrations of haloperidol, in predisposed patients, or with parenteral use, especially with intravenous administration.

Haloperidol decanoate should not be administered intravenously.

Caution is recommended when used in patients with bradycardia, heart disease, family history of prolonged QTc interval, or history of heavy alcohol consumption. Caution is also necessary when treating patients with potentially high plasma concentrations of haloperidol (see subsection below “Slow metabolizers of the CYP2D6 isoenzyme”).

ECG monitoring is recommended before starting treatment. During treatment, the need for ECG monitoring to detect QTc interval prolongation and ventricular arrhythmias should be assessed in all patients. Dose reduction is recommended if QTc prolongation occurs during treatment, and if QTc exceeds 500 ms, Haloperidol should be discontinued.

Electrolyte imbalances, such as hypokalemia and hypomagnesemia, increase the risk of ventricular arrhythmias and should be corrected before starting treatment with haloperidol. Preliminary and periodic monitoring of plasma electrolyte levels is recommended.

Tachycardia and arterial hypotension (including orthostatic hypotension) have also been reported (see section “Adverse Reactions”). Caution is recommended when prescribing haloperidol to patients with arterial hypotension or orthostatic hypotension.

Cerebrovascular events

In randomized placebo-controlled clinical trials, an approximately 3-fold increased risk of cerebrovascular adverse events was observed with the use of some atypical antipsychotic drugs in patients with dementia. Observational studies comparing the incidence of stroke in elderly patients receiving any antipsychotic drug and patients not taking such drugs revealed an increased incidence of stroke in the first group of patients. This incidence may be higher with the use of all butyrophenones, including Haloperidol. The mechanism of the increased risk has not been established. An increased risk in other patient groups cannot be excluded. Haloperidol decanoate should be used with caution in patients with risk factors for stroke.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome, a rare idiosyncratic reaction characterized by hyperthermia, generalized muscle rigidity, autonomic lability, impaired consciousness, and increased serum CPK activity, may develop with the use of haloperidol. An early sign of this syndrome is often hyperthermia. Treatment with antipsychotic drugs should be discontinued immediately and appropriate supportive therapy initiated under close supervision.

Tardive dyskinesia

Tardive dyskinesia may occur in some patients with long-term use or discontinuation of the drug. The syndrome is manifested mainly by rhythmic involuntary movements of the muscles of the tongue, face, lips or jaw. In some patients, the manifestations may be permanent. The syndrome may be masked upon resumption of treatment, upon dose increase, or upon switching to treatment with another antipsychotic drug. If signs and symptoms of tardive dyskinesia appear, the possibility of discontinuing all antipsychotic drugs, including Haloperidol decanoate, should be considered.

Extrapyramidal symptoms

Extrapyramidal symptoms (e.g., tremor, muscle rigidity, hypersalivation, bradykinesia, akathisia, acute muscle dystonia) may be observed. Akathisia may develop with the use of haloperidol, characterized by subjectively unpleasant or distressing restlessness and a need to be in constant motion, often accompanied by an inability to sit or stand still. Akathisia is most likely to develop within the first few weeks of treatment. For patients with such symptoms, increasing the dose may be dangerous.

Acute muscle dystonia may occur within the first few days of treatment with Haloperidol decanoate, but may also appear later or after a dose increase. Symptoms of muscle dystonia include: torticollis, grimacing, spasm of the masticatory muscles (trismus), tongue protrusion, and unusual eye movements, including oculogyric crisis. The risk of such reactions is higher in male patients and younger individuals. If acute muscle dystonia develops, the drug should be discontinued.

If necessary to relieve extrapyramidal symptoms, anticholinergic antiparkinsonian drugs can be used, but their use as a preventive measure is not recommended. If concomitant treatment with an antiparkinsonian drug is required, and it is eliminated faster than Haloperidol, its administration should be continued even after discontinuation of Haloperidol decanoate to avoid the development or exacerbation of extrapyramidal symptoms. When using anticholinergic drugs, including antiparkinsonian drugs, concomitantly with Haloperidol decanoate, the possibility of increased intraocular pressure should be kept in mind.

Seizures/convulsions

Haloperidol has been reported to cause seizures. Caution should be exercised when treating patients with epilepsy and in conditions predisposing to seizures (e.g., alcohol withdrawal syndrome, brain injury).

Disorders of the liver and biliary tract

Since Haloperidol is metabolized in the liver, dose reduction and precautionary measures are recommended when treating patients with hepatic insufficiency (see sections “Dosage Regimen” and “Pharmacokinetics”). Isolated cases of impaired liver function or hepatitis, most often cholestatic, have been reported (see section “Adverse Reactions”).

Endocrine system

Thyroxine may enhance the toxicity of haloperidol. Antipsychotic drugs should be used with caution in patients with hyperthyroidism and only in combination with therapy aimed at achieving a euthyroid state.

Hormonal effects of antipsychotic drugs include hyperprolactinemia, which may cause galactorrhea, gynecomastia and oligomenorrhea or amenorrhea (see section “Adverse Reactions”). Tissue culture studies indicate that prolactin may stimulate the growth of human breast tumor cells. Although no clear association between the use of antipsychotic drugs and human breast cancer has been established in clinical and epidemiological studies, caution is recommended when treating patients with a relevant medical history. Haloperidol decanoate should be used with caution in patients with pre-existing hyperprolactinemia and in patients with possible prolactin-dependent tumors.

Hypoglycemia and syndrome of inappropriate ADH secretion have been observed with the use of haloperidol (see section “Adverse Reactions”).

Venous thromboembolism

Cases of VTE have been reported with the use of antipsychotic drugs. Since patients taking antipsychotic drugs often have acquired risk factors for VTE, all possible VTE risk factors should be identified before and during treatment with Haloperidol decanoate and appropriate preventive measures taken.

Initiation of treatment

Patients planned to be treated with Haloperidol decanoate should first take Haloperidol orally to reduce the likelihood of unforeseen hypersensitivity to haloperidol.

Patients with depression

Haloperidol decanoate is not recommended as monotherapy in patients with predominant depressive symptoms. The drug can be combined with antidepressants to treat conditions characterized by a combination of depression and psychosis (see section “Drug Interactions”).

Slow metabolizers of the CYP2D6 isoenzyme

Haloperidol decanoate should be used with caution in patients who are slow metabolizers of the cytochrome P450 CYP2D6 isoenzyme and who are simultaneously taking CYP3A4 inhibitors.

Excipients

Haloperidol decanoate contains 15 mg of benzyl alcohol per 1 ml of solution. Benzyl alcohol may cause allergic reactions. In high doses, the drug should be used with caution and only when necessary, especially in patients with impaired liver or kidney function and/or in case of pregnancy or breastfeeding due to the risk of accumulation and toxicity (metabolic acidosis). Haloperidol decanoate contains sesame oil, which may rarely cause severe allergic reactions.

Effect on ability to drive vehicles and machinery

Haloperidol decanoate has a moderate effect on the ability to drive vehicles and machinery. Sedation or impaired concentration may be observed to varying degrees, especially with high doses and at the beginning of therapy. These effects are enhanced by alcohol. Patients should be advised to refrain from driving vehicles and from engaging in activities that require increased concentration and speed of psychomotor reactions during treatment with Haloperidol decanoate.

Overdose

Since overdose with parenteral administration is less likely than with oral administration, the following information relates to the oral form of haloperidol, also taking into account the prolonged action of haloperidol decanoate.

Symptoms: development of known pharmacological effects and adverse reactions in a more pronounced form. Overdose symptoms are severe extrapyramidal disorders, arterial hypotension and sedation. Extrapyramidal disorders are manifested by muscle rigidity and generalized or local tremor. Along with arterial hypotension, arterial hypertension may also develop.

In severe cases, the patient falls into a coma, with respiratory depression and arterial hypotension, the severity of which may correspond to a shock-like state. The risk of ventricular arrhythmias, possibly associated with QTc prolongation, should be assessed.

Treatment there is no specific antidote. Supportive therapy is carried out. The effectiveness of activated charcoal has not been established. Dialysis is not recommended for the treatment of overdose, as it removes a very small amount of haloperidol (see section “Pharmacokinetics”).

The airway patency in comatose patients must be ensured using an oropharyngeal airway or intubation. In case of respiratory depression, mechanical ventilation may be required.

ECG and vital signs monitoring is recommended until the ECG normalizes. Appropriate antiarrhythmic measures are recommended for the treatment of severe arrhythmias.

Arterial hypotension and vascular collapse can be compensated by intravenous infusion of fluids, plasma or concentrated albumin, as well as by the administration of vasoconstrictors such as dopamine or norepinephrine. The use of epinephrine is strictly not recommended, as in combination with haloperidol it may cause severe arterial hypotension.

If severe extrapyramidal symptoms develop, the use of antiparkinsonian drugs for several weeks is recommended. Antiparkinsonian drugs should be discontinued with great caution, as extrapyramidal symptoms may recur.

Drug Interactions

Interaction studies have been conducted only in adults.

Effect on the cardiovascular system

Concomitant use of Haloperidol decanoate with drugs that cause QTc interval prolongation is contraindicated (see section “Contraindications”). Examples of such drugs are

• Class I A antiarrhythmic drugs (e.g., disopyramide, quinidine).
• Class III antiarrhythmic drugs (amiodarone, dofetilide, dronedarone, ibutilide, sotalol).
• Some antidepressants (citalopram, escitalopram).
• Some antibiotics (azithromycin, clarithromycin, erythromycin, levofloxacin, moxifloxacin, telithromycin).
• Other antipsychotic drugs (phenothiazine derivatives, sertindole, pimozide, ziprasidone).
• Some antifungal drugs (pentamidine).
• Some antimalarial drugs (halofantrine).
• Some drugs affecting the gastrointestinal tract (dolasetron).
• Some drugs for the treatment of cancer (toremifene, vandetanib).
• Some other drugs (bepridil, methadone).

This list is not exhaustive.

Caution is recommended when using Haloperidol decanoate in combination with drugs that cause electrolyte imbalances (see section “Special Precautions”).

Drugs that may increase plasma concentrations of haloperidol

Haloperidol metabolism occurs via several pathways (see section “Pharmacokinetics”). The main pathway is glucuronidation and reduction to ketones. The cytochrome P450 isoenzyme system, especially CYP3A4 and, to a lesser extent, CYP2D6, is also involved in metabolism. Suppression of these metabolic pathways by another drug or reduced activity of the CYP2D6 isoenzyme may lead to increased plasma concentrations of haloperidol. An additive effect of suppression of CYP3A4 isoenzyme activity and reduced activity of the CYP2D6 isoenzyme is possible (see section “Pharmacokinetics”). Based on limited and, in some cases, conflicting information, the potential increase in plasma haloperidol concentration with concomitant use of a CYP3A4 and/or CYP2D6 isoenzyme inhibitor may range from 20 to 40%, although in some cases an increase of up to 100% has been recorded. Examples of drugs that may lead to increased plasma concentrations of haloperidol (based on clinical experience or mechanisms of drug interactions) are

• Inhibitors of the CYP3A4 isoenzyme – alprazolam, fluvoxamine, indinavir, itraconazole, ketoconazole, nefazodone, posaconazole, saquinavir, verapamil, voriconazole.
• Inhibitors of the CYP2D6 isoenzyme – bupropion, chlorpromazine, duloxetine, paroxetine, promethazine, sertraline, venlafaxine.
• Combined inhibitors of the CYP3A4 and CYP2D6 isoenzymes: fluoxetine, ritonavir.
• With an unspecified mechanism – buspirone.

This list is not exhaustive.

An increase in plasma concentrations of haloperidol may increase the risk of adverse events, including QTc interval prolongation (see the “Special Precautions” section). QTc interval prolongation was observed with the use of haloperidol in combination with metabolism inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day).

In patients taking Haloperidol concurrently with such drugs, monitoring for signs or symptoms of intensified or prolonged pharmacological action of haloperidol is recommended, and the dose of Haloperidol decanoate should be reduced if necessary.

Drugs that may decrease plasma concentrations of haloperidol

Concomitant use of haloperidol with potent inducers of the CYP3A4 isoenzyme may lead to a gradual decrease in plasma concentrations of haloperidol to such an extent that its efficacy will also decrease. Examples of such drugs are: carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort (Hypericum perforatum). The list is not exhaustive.

Enzyme induction can be observed within a few days of drug use. Maximum enzyme induction is usually observed after approximately 2 weeks and may persist for some time after discontinuation of the drug therapy. When using inducers of the CYP3A4 isoenzyme concomitantly, patient monitoring is recommended, and the dose of Haloperidol decanoate should be increased if necessary. After discontinuation of the CYP3A4 isoenzyme inducer, the concentration of haloperidol may gradually increase, consequently, it may be necessary to reduce the dose of Haloperidol decanoate.

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

Effect of haloperidol on other drugs

Haloperidol may potentiate the effect of CNS depressants, including alcohol, hypnotics, sedatives, and strong analgesics. Potentiation of CNS effects has also been noted when combined with methyldopa.

Haloperidol antagonizes the effects of epinephrine and other drugs with sympathomimetic activity (e.g., stimulants like amphetamines) and reverses the antihypertensive effect of adrenergic blockers such as guanethidine.

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

Haloperidol is an inhibitor of the CYP2D6 isoenzyme. Haloperidol inhibits the metabolism of tricyclic antidepressants (such as imipramine, desipramine), thereby contributing to an increase in their plasma concentrations.

Other forms of interaction

In rare cases, the following disorders have been observed with the concomitant use of lithium salts and haloperidol: encephalopathy, extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, acute brain syndrome, and coma. Most of these symptoms are reversible. Whether these symptoms represent a specific nosological entity is not yet clear.

Nevertheless, if such symptoms appear in patients taking lithium salts and Haloperidol concomitantly, the use of the drugs should be discontinued immediately.

Antagonism of haloperidol towards the anticoagulant phenindione has been identified.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging to protect from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 5 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.