Each ml of Haldol Decanoas 50 mg/ml is expressed in terms of the haloperidol content and is equivalent to 70.52 mg haloperidol decanoate.
Excipients/Inactive Ingredients: Benzyl alcohol, sesame oil refined.
Pharmacotherapeutic group: antipsychotics. ATC Code: N05AD01.
Pharmacology: Pharmacodynamics: Mechanism of action: Haloperidol decanoate is an ester of haloperidol and decanoic acid, and as such, a depot antipsychotic belonging to the butyrophenones group. After intramuscular injection, haloperidol decanoate is gradually released from muscle tissue and hydrolyzed slowly into free haloperidol which enters the systemic circulation.
Haloperidol is a potent central dopamine type 2 receptor antagonist, and at recommended dosages, has low alpha 1 antiadrenergic activity and no antihistaminergic or anticholinergic activity.
Pharmacodynamic effects: Haloperidol suppresses delusions and hallucinations as a direct consequence of blocking dopaminergic signaling in the mesolimbic pathway. The central dopamine blocking effect has activity on the basal ganglia (nigrostriatal bundles). Haloperidol causes effective psychomotor sedation, which explains the favourable effect on manias.
The activity on the basal ganglia probably underlies the undesirable extrapyramidal motor effects (dystonia, akathisia and parkinsonism).
The antidopaminergic effects of haloperidol on lactotropes in the anterior pituitary explain hyperprolactinemia due to inhibition of dopamine mediated tonic inhibition of prolactin secretion.
Clinical studies: In clinical studies, patients were mostly reported to have received prior treatment with orally administered haloperidol before converting to haloperidol decanoate. Occasionally, patients had previously been treated orally with another antipsychotic medicinal product.
Pharmacokinetics: Absorption: Administration of haloperidol decanoate as a depot intramuscular injection results in a slow and sustained release of free haloperidol. The plasma concentrations rise gradually, usually peaking within the first week after injection.
Steady state plasma levels are reached within 2 to 4 months in patients receiving monthly injections.
Distribution: Mean haloperidol plasma protein binding in adults is approximately 88 to 92%. There is a high inter subject variability for plasma protein binding. Haloperidol is rapidly distributed to various tissues and organs, as indicated by the large volume of distribution (mean values 8 to 21 L/kg after intravenous dosing). Haloperidol crosses the blood brain barrier easily. It also crosses the placenta and is excreted in breast milk.
Metabolism: Haloperidol is extensively metabolized in the liver. The main metabolic pathways of haloperidol in humans include glucuronidation, ketone reduction, oxidative N dealkylation and formation of pyridinium metabolites. The metabolites of haloperidol are not considered to make a significant contribution to its activity. The cytochrome P450 enzymes CYP3A4 and CYP2D6 are involved in haloperidol metabolism. Inhibition or induction of CYP3A4, or inhibition of CYP2D6, may affect haloperidol metabolism. A decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations.
Excretion: The terminal elimination half-life of haloperidol after intramuscular injection with haloperidol decanoate is on average 3 weeks. This is longer than for the non-decanoate formulations, where the haloperidol terminal elimination half-life is on average 24 hours. Haloperidol apparent clearance after extravascular administration ranges from 0.9 to 1.5 L/h/kg and is reduced in poor metabolizers of CYP2D6 substrates. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia. After intravenous haloperidol administration, 21% of the dose was eliminated in the feces and 33% in the urine. Less than 3% of the dose is excreted unchanged in the urine.
Linearity/non-linearity: The pharmacokinetics of haloperidol following intramuscular injections of haloperidol decanoate are dose related. The relationship between dose and plasma haloperidol level is approximately linear for doses below 450 mg.
Pharmacokinetic/pharmacodynamics relationships: Therapeutic concentrations: Based on clinical studies with haloperidol, therapeutic response is obtained in most patients with acute or chronic schizophrenia at plasma concentrations of 1 to 10 ng/mL, while some patients may require concentrations up to 17 ng/mL.
In patients with first episode schizophrenia treated with short acting haloperidol formulations, therapeutic response may be obtained at concentrations as low as 0.6 to 3.2 ng/mL, as estimated based on measurements of D2 receptor occupancy and assuming that a D2 receptor occupancy level of 60 to 80% is most appropriate for obtaining therapeutic response and limiting extrapyramidal symptoms.
Due to the high inter subject variability in haloperidol pharmacokinetics and the concentration effect relationship, it is recommended to adjust the individual haloperidol decanoate dose based on the patient's response. This must take into account the time after a change in dose to achieve a new steady state plasma concentration and the additional time to elicit a therapeutic response.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazards for humans based on conventional studies of local tolerability, repeat dose toxicity, genotoxicity and carcinogenicity. In rodents, haloperidol administration showed a decrease in fertility, limited teratogenicity as well as embryo-toxic effects.
Haloperidol has been shown to block the cardiac hERG channel in several published studies in vitro. In a number of in vivo studies intravenous administration of haloperidol in some animal models has caused significant QTc interval prolongation, at doses around 0.3 mg/kg i.v., giving Cmax plasma levels 4 to 8 times higher than the maximum therapeutic plasma concentration of 17 ng/mL in clinical studies. These intravenous doses which prolonged QTc did not cause arrhythmias. In some animal studies higher intravenous haloperidol doses of 1 mg/kg or greater caused QTc prolongation and/or ventricular arrhythmias at Cmax plasma levels 22 to 81 times higher than the maximum therapeutic plasma concentration in clinical studies.
Haldol Decanoas is indicated for the maintenance treatment of chronic schizophrenia and other psychoses.
Patients must be previously stabilized on oral haloperidol before converting to Haldol Decanoas.
Haldol Decanoas is for intramuscular use only and must not be administered intravenously (see Instructions for use/handling under Cautions for Usage).
Haldol Decanoas is administered as a deep intramuscular injection in the gluteal region. It is recommended to alternate between the two gluteal muscles for subsequent injections. As the administration of volumes greater than 3 ml is uncomfortable for the patient, such large injection volumes are not recommended.
Treatment initiation and dose titration must be carried out under close clinical supervision.
The individual dose will depend on both the severity of the symptoms and the current oral haloperidol dose. Patients must always be maintained on the lowest effective dose.
It is recommended that the initial dose of Haldol Decanoas be 10-15 times the previous daily dose of oral haloperidol. For most patients, this means a starting dose ranging between 25 and 75 mg of Haldol Decanoas. A maximum starting dose of 100 mg should not be exceeded.
Depending on the individual patient's response the dose may gradually be increased by 50 mg until an optimal therapeutic effect is obtained. The most appropriate monthly dose of Haldol Decanoas is often about 20 times the daily dose of oral haloperidol. During dose adjustment or episodes of exacerbation of psychotic symptoms, Haldol Decanoas therapy can be supplemented with regular haloperidol.
The usual time interval between injections is 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval.
Elderly and debilitated patients: It is recommended to start with low doses, for example 12.5 mg-25 mg every 4 weeks, only increasing the dose according to the patient's response.
Maintenance therapy: The maintenance dosage of haloperidol decanoate must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patients.
While overdosage is less likely to occur with parenteral than with oral medication, information pertaining to oral haloperidol is presented, modified only to reflect the extended duration of action of Haldol Decanoas.
Symptoms and signs: The manifestations of haloperidol overdose are an exaggeration of the known pharmacological effects and adverse reactions. The most prominent symptoms are: severe extrapyramidal reactions, hypotension, and sedation. An extrapyramidal reaction is manifest by muscular rigidity and a generalized or localized tremor. Hypertension rather than hypotension is also possible. In extreme cases, the patient would appear comatose with respiratory depression and hypotension that could be severe enough to produce a shock-like state. The risk of ventricular arrhythmias, possibly associated with QTc interval prolongation, should be considered.
Treatment: There is no specific antidote. Treatment is supportive. For comatose patients, a patent airway should be established by use of an oropharyngeal airway or endotracheal tube. Respiratory depression may necessitate artificial respiration.
ECG and vital signs should be monitored and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures.
Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as dopamine or noradrenaline (norepinephrine). Adrenaline (epinephrine) must not be used because it might cause profound hypotension in the presence of haloperidol.
In case of severe extrapyramidal reactions, antiparkinson medication should be administered and continued for several weeks. Antiparkinson medication must be withdrawn very cautiously as extrapyramidal symptoms may emerge.
Known hypersensitivity to haloperidol or to any of the excipients; Comatose state; Central Nervous System (CNS) depression due to alcohol or other depressant drug; Parkinson's disease; Dementia with Lewy bodies; Progressive supranuclear palsy.
Since haloperidol is metabolized in the liver, caution is advised in patients with liver diseases.
Mortality: Rare cases of sudden death have been reported in psychiatric patients receiving antipsychotic drugs, including Haldol Decanoas (see Adverse Reactions).
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients has not yet been elucidated.
Cardiovascular effects: Very rare reports of QTc interval prolongation and/or ventricular arrhythmias, in addition to rare reports of sudden death, have been reported with haloperidol (see Adverse Reactions). They may occur more frequently with high doses, in predisposed patients, or with a QTc interval that exceeds 500 ms.
As QTc interval prolongation has been observed during haloperidole treatment, caution is advised in patients with QTc-prolonging conditions (long QT-syndrome, hypokalaemia, hypomagnesemia, electrolyte imbalance, drugs known to prolong QTc, cardiovascular diseases, family history of QTc prolongation), especially if haloperidol is given parenterally (see Cardiovascular effects under Interactions).
The risk of QTc prolongation and/or ventricular arrhythmias may be increased with higher doses or with parenteral use, particularly intravenous administration.
Haloperidol decanoate must not be administered intravenously.
Tachycardia and hypotension (including orthostatic hypotension) have also been reported in occasional patients (see Adverse Reactions).
Cerebrovascular events: In randomized, placebo controlled clinical trials in the dementia population, there was an approximately 3 fold increased risk of cerebrovascular adverse events with some atypical antipsychotics. Observational studies comparing the stroke rate in elderly patients exposed to any antipsychotic to the stroke rate in those not exposed to such medicinal products reported an increased stroke rate among exposed patients. This increase may be higher with all butyrophenones, including haloperidol. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other patient populations. Haldol Decanoas must be used with caution in patients with risk factors for stroke.
Neuroleptic malignant syndrome: In common with other antipsychotic drugs, Haldol Decanoas has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterized by hyperthermia, generalized muscle rigidity, autonomic instability, altered consciousness, and increased serum creatine phosphokinase levels. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.
Tardive dyskinesia: As with all antipsychotic drugs, tardive dyskinesia may appear in some patients on long-term therapy or after drug discontinuation. The syndrome is mainly characterized by rhythmic involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dosage is increased or when a switch is made to a different antipsychotic drug. Treatment should be discontinued as soon as possible.
Extrapyramidal symptoms: In common with all antipsychotic drugs, extrapyramidal symptoms may occur (e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia).
Antiparkinson drugs of the anticholinergic type may be prescribed as required, but should not be prescribed routinely as a preventive measure. If concomitant antiparkinson medication is required, it may have to be continued after stopping Haldol Decanoas if its excretion is faster than that of haloperidol to avoid the development or aggravation of extrapyramidal symptoms. The possible increase in intraocular pressure must be considered when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with Haldol Decanoas.
Seizures/convulsions: It has been reported that seizures can be triggered by Haldol Decanoas. Caution is advised in patients suffering from epilepsy and in conditions predisposing to convulsions (e.g., alcohol withdrawal and brain damage).
Hepatobiliary concerns: As haloperidol is metabolized by the liver, caution is advised in patients with liver disease. Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported (see Adverse Reactions).
Endocrine system concerns: Thyroxin may facilitate haloperidol toxicity. Antipsychotic therapy in patients with hyperthyroidism should be used only with caution and must always be accompanied by therapy to achieve a euthyroid state.
Hormonal effects of antipsychotic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligomenorrhea or amenorrhoea. Very rare cases of hypoglycaemia and of syndrome of inappropriate antidiuretic hormone secretion have been reported (see Adverse Reactions).
Venous thromboembolism: Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Haldol Decanoas and preventive measures undertaken.
Treatment initiation: Patients being considered for Haldol Decanoas therapy must be initially treated with oral haloperidol to exclude the possibility of an unexpected adverse sensitivity to haloperidol.
Patients with depression: As with all antipsychotic drugs, Haldol Decanoas should not be used alone where depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist (see Interactions).
Effects on Ability to Drive and Use Machines: Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment and may be potentiated by alcohol. Patients should be advised not to drive or operate machinery during treatment, until their susceptibility is known.
Pregnancy: Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms that may vary in severity following delivery. These symptoms in neonates may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. These complications have varied in severity; while in some cases symptoms have been self-limited; in other cases neonates have required additional medical treatment or monitoring.
Haldol Decanoas has shown no significant increase in fetal anomalies in large population studies. There have been isolated case reports of birth defects following fetal exposure to Haldol Decanoas in combination with other drugs. Animal studies have demonstrated a teratogenic effect of haloperidol (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Haldol Decanoas should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.
Breast-feeding: Haloperidol is excreted in breast milk. Small amounts of haloperidol have been detected in plasma and urine of breast fed newborns of mothers treated with haloperidol. If the use of Haldol Decanoas is considered essential, the benefits of breast-feeding should be balanced against its potential risks.
Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of haloperidol decanoate (or non-decanoate formulations) based on the comprehensive assessment of the available adverse event information. A causal relationship with haloperidol decanoate (or non-decanoate formulations) cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical trial data: Comparator and open-label trial data - adverse drug reactions reported at ≥ 1% incidence:
The safety of Haldol Decanoas (15-500 mg/month) was evaluated in 410 subjects who participated in 13 clinical trials in the treatment of schizophrenia or a schizoaffective disorder.
Adverse Reactions reported by ≥ 1% of Haldol Decanoas-treated subjects in these trials are shown in Table 1. (See Table 1.)
Click on icon to see table/diagram/image
Comparator and open-label trial data - adverse drug reactions reported at <1% incidence:
Additional adverse reactions that occurred in <1% of Haldol Decanoas-treated subjects either of the previous trial data are listed as follows in Table 2. (See Table 2.)
Click on icon to see table/diagram/image
Adverse reactions identified in clinical trials with haloperidol (non-decanoate formulations):
Adverse reactions relating to the active moiety that were identified in clinical trials with haloperidol (non-decanoate formulations) are listed in Table 3. (See Table 3.)
Click on icon to see table/diagram/image
Adverse events first identified as adverse reactions during postmarketing experience with haloperidol are included in Table 4. The postmarketing review was based on review of all cases including haloperidol and haloperidol decanoate-containing products. In each table, the frequencies are provided according to the following convention: Very common ≥ 1/10; Common ≥ 1/100 to < 1/10; Uncommon ≥ 1/1,000 to < 1/100; Rare ≥ 1/10,000 to < 1/1,000; Very rare < 1/10,000, including isolated reports.
In Table 4, adverse reactions are presented by frequency category based on spontaneous reporting rates, when known. (See Table 4.)
Click on icon to see table/diagram/image
Cardiovascular effects: As with other antipsychotic drugs, caution is advised when Haldol Decanoas is used in combination with medications known to prolong the QTc interval (see Cardiovascular effects under Precautions). 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. erythromycin, levofloxacin, moxifloxacin).
Certain antifungals (e.g. pentamidine).
Certain antimalarials (e.g. halofantrine).
Certain gastrointestinal drugs (e.g. dolasetron).
Certain drugs used in cancer (e.g. toremifene, vandetanib).
Certain other drugs (e.g. bepridil, methadone).
This list is not exhaustive.
It is recommended that concomitant use of other antipsychotic drugs be avoided.
Caution is advised when Haldol Decanoas is used in combination with drugs known to cause electrolyte imbalance (see Cardiovascular effects under Precautions).
Drugs that may increase haloperidol plasma concentrations: Haloperidol is metabolized by several routes (see Pharmacology: Pharmacokinetics: Metabolism under Actions). 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 drug or a decrease in CYP 2D6 enzyme activity may result in increased haloperidol concentrations. The effect of CYP3A4 inhibition and of decreased CYP2D6 enzyme activity may be additive (see Pharmacology: Pharmacokinetics: Metabolism under Actions). Based on limited and sometimes conflicting information, the average increase in haloperidol plasma concentrations when a CYP3A4 and/or CYP2D6 inhibitor was coadministered generally ranged between 20 and 40%, although in some cases, average increases of up to 100% have been reported. Examples of drugs that may increase haloperidol plasma concentrations (based on clinical experience or drug interaction mechanism) include: CYP3A4 inhibitors - alprazolam; itraconazole, ketoconazole, and some other azoles; nefazodone; certain antivirals.
CYP2D6 inhibitors - chlorpromazine; promethazine; quinidine; paroxetine, sertraline, venlafaxine, and some other antidepressants.
Combined CYP3A4 and CYP2D6 inhibitors - fluoxetine, fluvoxamine; ritonavir.
Uncertain mechanism - buspirone.
This list is not exhaustive.
Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTc interval prolongation (see Cardiovascular effects under Precautions). 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 Decanoas dose be decreased as deemed necessary.
Sodium valproate, a drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.
Drugs 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 (based on clinical experience or drug interaction mechanism) 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. Therefore, during combination treatment with inducers of CYP3A4, it is recommended that patients be monitored and the Haldol Decanoas dose increased or the dosage interval adjusted, 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 dose of Haldol Decanoas, or adjust the dosage interval.
Effect of other drugs on haloperidol: In common with all antipsychotics drugs, haloperidol can increase the CNS depression produced by other CNS-depressant drugs, including alcohol, hypnotics, sedatives or analgesics. An enhanced CNS effect, when combined with methyldopa, has been reported.
Haloperidol may antagonize the action of adrenaline and other sympathomimetic agents and reverse the blood-pressure-lowering effects of adrenergic-blocking agents such as guanethidine.
Haloperidol may impair the antiparkinson effects of levodopa and other dopamine agonist drugs.
Haloperidol is an inhibitor of CYP 2D6. it inhibits the metabolism of tricyclic antidepressants, thereby increasing plasma levels of these drugs.
Other forms of interaction: In rare cases the following symptoms were reported during the concomitant use of lithium and haloperidol decanoate: encephalopathy, extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome, brain stem disorder, acute brain syndrome and coma. Most of these symptoms were reversible.
Nonetheless, it is advised that in patients, who are treated concomitantly with lithium and Haldol Decanoas, therapy must be stopped immediately if such symptoms occur.
Antagonism of the anticoagulant effect of phenindione has been reported.
Instructions for use/handling: Before use, roll the ampoule between the palms of the hands for a moment to warm it up.
1. Hold the ampoule between the thumb and index finger, leaving the tip of the ampoule free.
2. With the other hand, hold the tip of ampoule putting the index finger against the neck of ampoule, and the thumb on the colored point in parallel to the identification colored ring(s).
3. Keeping the thumb on the point, sharply break the tip of ampoule while holding firmly the other part of the ampoule in the hand.
Incompatibilities: Due to the oily base, this injectable solution may not be used in infusions.
Store below 30°C.
Protect from light.
Shelf Life: 3 years.
N05AD01 - haloperidol ; Belongs to the class of butyrophenone derivatives antipsychotics.
Haldol Decanoas inj 50 mg/mL
1 mL x 5 × 1's (Rp747,290/boks)