Each 1ml Solution for injection contains 70.52mg Haloperidol Decanoate (equivalent to 50mg Haloperidol base), or 141.04mg haloperidol Decanoate, equivalent to 100mg Haloperidol base
Mechanism of action:
Haloperidol decanoate is an ester of haloperidol and decanoic acid, and as such, a depot antipsychotic belonging to the butyrophenones group.
Haloperidol is a potent central dopamine type 2 receptor antagonist
After intramuscular injection, haloperidol decanoate is gradually released from muscule tissue and hydrolysed slowly into free haloperidol, which enters the systemic circulation.
Pharmacokenitic Properities:
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 3 to 9 days 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%. Haloperidol is rapidly distributed to various tissues and organs.
Haloperidol crosses the blood-brain barrier easily. It also crosses the placenta and is excreted in breast milk.
Elimination: 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 after oral administration and 21 hours after intramuscular administration.
Haloperidol apparent clearance after extravascular administration ranges from 0.9 to 1.5 l/h/kg.
Indications:
Hyalolong is indicated for the maintenance treatment of schizophrenia and schizoaffective disorder in adult patients currently stabilised with oral haloperidol.
Contraindications:
• Hypersensitivity to the active substance or to any of the excipients.
• Comatose state.
• Central nervous system (CNS) depression.
• Parkinson's disease.
• Dementia with Lewy bodies.
• Progressive supra nuclear palsy.
•Known QTc interval prolongation or congenital long QT syndrome.
• Recent and Uncompensated acute myocardial infarction.
• Uncompensated heart failure.
• History of ventricular arrhythmia.
• Uncorrected hypokalaemia.
• Concomitant treatment with medicinal products that prolong the QT interval
Special warnings and precautions:
• Increased mortality in elderly people with dementia: Rare cases of sudden death have been reported in psychiatric patients receiving antipsychotics, including haloperidol.
• Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death.
• Haloperidol solution for injection is not indicated for the treatment of dementia-related behavioural disturbances.
• Cardiovascular effects, QTc prolongation and/or ventricular arrhythmias, in addition to sudden death, have been reported with haloperidol The risk of these events appears to increase with high doses, high plasma concentrations, in predisposed patients or with parenteral use, particularly intravenous administration.
• Haloperidol solution for injection is recommended for intramuscular administration only. However, if administered intravenously,
continuous ECG monitoring must be performed for QTc interval prolongation and for ventricular arrhythmias.
• Caution is advised in patients with bradycardia, cardiac disease, family history of QTc prolongation or history of heavy alcohol exposure. Caution is also required in patients with potentially high plasma concentrations.
• A baseline ECG is recommended before intramuscular dosing. During therapy, the need for ECG monitoring for QTc interval prolongation and for ventricular arrhythmias must be assessed in all patients, but continuous ECG monitoring is recommended
for repeated intramuscular doses. ECG monitoring is recommended up to 6 hours after administration of Haloperidol solution
for injection to patients for prophylaxis or treatment of postoperative nausea and vomiting.
• Whilst on therapy, it is recommended to reduce the dose if QTc is prolonged, but haloperidol must be discontinued if the QTc exceeds 500ms.
• Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for ventricular arrhythmias and must be corrected before treatment with haloperidol is started. Therefore, baseline and periodic electrolyte monitoring is recommended.
• Tachycardia and hypotension (including orthostatic hypotension) have also been reported. Caution is recommended when haloperidol is administered to patients manifesting hypotension or orthostatic hypotension.
Cerebrovascular events:
- In randomised, placebo-controlled clinical studies in the dementia population, there was an approximately 3-fold increased risk
of cerebrovascular adverse events with some atypical antipsychotics.
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.
- Haloperidol must be used with caution in patients with risk factors for stroke.
Neuroleptic malignant syndrome:
- Haloperidol 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 must be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.
Tardive dyskinesia:
- Tardive dyskinesia may appear in some patients on long-term therapy or after discontinuation of the medicinal product.
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 dose is increased.
or when a switch is made to a different antipsychotic. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including haloperidol, must be considered.
Extrapyramidal symptoms:
- Extrapyramidal symptoms may occur (e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia). The use of
haloperidol has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing
restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first
few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
- Acute dystonia may occur during the first few days of treatment with haloperidol, but later onset as well as onset after dose increases has been
reported. Dystonic symptoms can include, but are not limited to, torticollis, facial grimacing, trismus, tongue protrusion, and abnormal eye movements, including oculogyric crisis. Males and younger age groups are at higher risk of experiencing such reactions. Acute dystonia may necessitate stopping the medicinal product.
- Antiparkinson medicinal products of the anticholinergic type may be prescribed as required to manage extrapyramidal symptoms, but it is
recommended that they are not prescribed routinely as a preventive measure. If concomitant treatment with an antiparkinson medicinal product is required, it may have to be continued after stopping haloperidol if its excretion is faster than that of haloperidol in order to avoid the development or aggravation of extrapyramidal symptoms. The possible increase in intraocular pressure must be considered when anticholinergic medicinal products, including antiparkinson medicinal products, are administered concomitantly with haloperidol.
Seizures/Convulsions:
- It has been reported that seizures can be triggered by Haloperidol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to seizures (e.g. alcohol withdrawal and brain damage).
Hepatobiliary concerns:
As haloperidol is metabolised by the liver, half the initial dose and caution is advised in patients with hepatic impairment.
Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported.
Endocrine system concerns:
- Thyroxin may facilitate Haloperidol toxicity. Antipsychotic therapy in patients with hyperthyroidism must be used only with caution and must always be accompanied by therapy to achieve a euthyroid state.
- Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia
and oligo or amenorrhoea. Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics and human breast tumours has been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history.
- Haloperidol must be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent
tumours.
- Hypoglycaemia and syndrome of inappropriate antidiuretic hormone secretion have been reported with haloperidol.
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 Haloperidol and preventive measures undertaken.
Treatment initiation:
Patients being considered for HALOPERIDOL Decanoate therapy must be initially treated with oral haloperidol to reduce the possibility of an unexpected adverse sensitivity to haloperidol.
Patients with depression:
• It is recommended that haloperidol is not used alone in patients in whom depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist.
Switch from mania to depression:
• There is a risk in the treatment of manic episodes of bipolar disorder for patients to switch from mania to depression. Monitoring of patients for the switch to a depressive episode with the accompanying risks such as suicidal behaviour is important in order to intervene when such switches occur.
Poor metabolisers of CYP2D6:
Haloperidol should be used with caution in patients who are known poor metabolisers of cytochrome P450 (CYP) 2D6 and who are coadministered a CYP3A4 inhibitor
Effects on ability to drive and use machines:
Haloperidol has a moderate influence on the 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. It is recommended that patients be advised not to drive or operate machines during treatment, until their susceptibility is known
Pregnancy & Lactation:
It is preferable to avoid the use of haloperidol Decanoate during pregnancy
Haloperidol is excreted in human milk, A decision must be made whether to discontinue breastfeeding or to discontinue haloperidol therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Side effects:
Very Common (≥ 1/10): extrapyramidal disorder, hyperkinesias, tremor, parkinsonism , muscle rigidity , and somnolence.
Common (≥ 1/100 to < 1/10): Depression, Insomnia ,Akathisia,
Masked facies, Sedation ,Constipation ,Dry mouth ,Salivary hypersecretion , Sexual dysfunction ,Injection site reaction ,Weight increased.
Uncommon: Akinesia ,Dyskinesia ,Dystonia ,Cogwheel rigidity
Hypertonia ,Headache ,Oculogyric crisis ,Vision blurred ,Visual disturbance, Tachycardia.
Drug Interactions:
Haloperidol is contraindicated in combination with medicinal products known to prolong the QT
Class IA antiarrhythmics (e.g. disopyramide, quinidine).
Class III antiarrhythmics (e.g. amiodarone, dofetilide, dronedarone, ibutilide,
Certain Antidepressants: citalopram. escitalopram
Certain antibiotics: azithromycin, clarithromycin, levofloxacin, erythromycin
Other antipsychotics: phenothiazine derivatives, pimozide, ziprasidone
Certain antifungals:pentamidine
Certain antimalarials: halofantrine
Certain gastrointestinal medicinal products: dolasetron
Certain medicinal products used in cancer: toremifene, vandetanib
other medicinal products: bepridil, methadone
2- Medicinal products that may increase haloperidol plasma concentrations:
CYP3A4 inhibitors: alprazolam, fluvoxamine, itraconazole, ketoconazole, Verapamil. voriconazole.
CYP2D6 inhibitors: bupropion, chlorpromazine, paroxetine, promethazine, sertraline, venlafaxine.
Combined CYP3A4 and CYP2D6 inhibitors: fluoxetine, ritonavir.
Uncertain mechanism: buspirone.
3- Medicinal products that may decrease haloperidol plasma concentrations:
enzyme inducers of CYP3A4 such as: Carbamazepine, phenobarbital, phenytoin, rifampicin.
4- Effect of haloperidol on other medicinal products:
- Haloperidol can increase the CNS depression produced by alcohol or CNS-depressant medicinal products
- Haloperidol may antagonise the action of adrenaline and other sympathomimetic medicinal products
- Haloperidol may antagonise the effect of levodopa and other dopamine agonists.
- Haloperidol inhibits the metabolism of tricyclic antidepressants,
thereby increasing plasma concentrations of these medicinal products.
Dosage and administration:
- 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.
- As the initial dose of haloperidol decanoate is based on a multiple of the
daily oral haloperidol dose.
1- Adults aged 18 years and above:
Transition from oral haloperidol: A haloperidol decanoate dose of 10 to 15 times the previous daily dose of oral haloperidol is recommended.
Based on this conversion, the haloperidol decanoate dose will be 25 to150 mg for most patients.
- Continuation of treatment:
- It is recommended to adjust the haloperidol decanoate dose by up to 50 mg every 4 weeks (based on individual patient response) until an optimal therapeutic effect is obtained.
- The most effective dose is expected to range between 50 and 200 mg.
- It is recommended to assess the individual benefit-risk when considering doses above 200 mg every 4 weeks.
- A maximum dose of 300 mg every 4 weeks must not be exceeded
because the safety concerns outweigh the clinical benefits of treatment.
- Dosing interval:
- Usually 4 weeks between injections.
- Adjustment of the dosing interval may be required (based on individual patient response).
- Supplementation with non-decanoate haloperidol:
- Supplementation with non-decanoate haloperidol may be considered
during transition to HALOPERIDOL Decanoate, dose adjustment or episodes of
exacerbation of psychotic symptoms (based on individual patien
response).
- The combined total dose of haloperidol from both formulations must not
exceed the corresponding maximum oral haloperidol dose of 20 mg/day.
2- Elderly:
- Transition from oral haloperidol: A low haloperidol decanoate dose of 12.5 to 25 mg is recommended.
- Continuation of treatment:
- It is recommended only to adjust the haloperidol decanoate dose if required (based on individual patient response) until an optimal therapeutic effect is obtained.
- The most effective dose is expected to range between 25 and 75mg.
- Doses above 75 mg every 4 weeks should only be considered in patients
who have tolerated higher doses and after reassessment of the patient's
individual benefit-risk profile.
- Dosing interval:
- Usually 4 weeks between injections.
- Adjustment of the dosing interval may be required (based on individual patient response).
- Supplementation with non-decanoate haloperidol:
- Supplementation with non-decanoate haloperidol may be considered
during transition to HALOPERIDOL Decanoate, dose adjustment or episodes of
exacerbation of psychotic symptoms (based on individual patient
response).
- The combined total dose of haloperidol from both formulations must not
exceed the corresponding maximum oral dose of haloperidol 5mg/day or
the previously administered oral haloperidol dose in patients who have
received longterm treatment with oral haloperidol.
3- Renal impairment:
- No dose adjustment is recommended, but caution is advised when
treating patients with renal impairment.
- However, patients with severe renal impairment may require a lower initial dose.
4- Hepatic impairment:
haloperidol is extensively metabolised in the liver, it is recommended to
halve the initial dose, and adjust the dose with smaller increments and at
longer intervals than in patients without hepatic impairment.
5- Paediatric population:
The safety and efficacy of HALOPERIDOL Decanoate in children and adolescents below 18 years of age have not been established.
Method of administration: HALOPERIDOL Decanoate is for intramuscular use only and must not be administered intravenously.
Overdose:
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 generalised or localised 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 prolongation, must be considered.
Treatment:
There is no specific antidote. Treatment is supportive. Dialysis is not
recommended in the treatment of overdose because it removes only very small amounts of haloperidol.
For comatose patients, a patent airway must be established by use of an
oropharyngeal airway or endotracheal tube.
Respiratory depression may necessitate artificial respiration.
It is recommended that ECG and vital signs be monitored, and that
monitoring continues until the ECG is normal. Treatment of severe
arrhythmias with appropriate anti-arrhythmic measures is recommended.
Hypotension and circulatory collapse may be counteracted by use of
intravenous fluids, plasma or concentrated albumin and vasopressor
agents, such as dopamine or noradrenaline. Adrenaline must not be used
because it might cause profound hypotension in the presence of
haloperidol.
In cases of severe extrapyramidal reactions, parenteral administration of
an antiparkinson medicinal product is recommended.