HALOPERIDOL DECANOATE_- haloperidol decanoate_injection

Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL are the long-acting forms of haloperidol, an antipsychotic. The mechanism of action of haloperidol for the treatment of schizophrenia is unclear. However, its efficacy could be mediated through its activity as an antagonist at central dopamine type 2 receptors. Haloperidol also binds to alpha-1 adrenergic receptors, but with lower affinity, and displays minimal binding to muscarinic cholinergic and histaminergic (H 1

Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL are indicated for the treatment of patients with schizophrenia who require prolonged parenteral antipsychotic therapy.

Haloperidol decanoate injection, 50 mg/mL or haloperidol decanoate injection, 100 mg/mL should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY. Initial Therapy Maintenance Therapy HALOPERIDOL DECANOATE DOSING RECOMMENDATIONS Patients Monthly 1 st Maintenance Stabilized on low daily oral doses 10 to 15 × Daily Oral Dose 10 to 15 × Previous Daily Oral Dose Close clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy. Haloperidol decanoate is usually administered monthly or every 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (see CLINICAL PHARMACOLOGY Clinical experience with haloperidol decanoate at doses greater than 450 mg per month has been limited.

Cerebrovascular Adverse Reactions
In controlled trials, elderly patients with dementia-related psychosis treated with some antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for haloperidol decanoate injection, other antipsychotics, or other patient populations. Haloperidol decanoate injection should be used with caution in patients with risk factors for cerebrovascular adverse reactions.
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs (see ADVERSE REACTIONS not
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs (see ADVERSE REACTIONS
Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy Bodies
Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity with haloperidol treatment include severe extrapyramidal symptoms, confusion, sedation, and falls. In addition, haloperidol may impair the antiparkinson effects of levodopa and other dopamine agonists. Haloperidol decanoate is contraindicated in patients with Parkinson’s Disease or Dementia with Lewy Bodies (see CONTRAINDICATIONS
Leukopenia,Neutropenia, and Agranulocytosis
Class Effect: Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of haloperidol decanoate should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. 3
ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling: Increased mortality in Elderly Patients with Dementia-Related Psychosis Cardiovascular Effects Tardive Dyskinesia Neuroleptic Malignant Syndrome Hypersensitivity Reactions Falls Combined Use of Haloperidol and Lithium General Leukopenia, Neutropenia, and Agranulocytosis Other Usage in Pregnancy Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice. Table 1: Adverse Reactions Reported by >=1% of Haloperidol Decanoate-Treated Patients in a Double-Blind Active Comparator-Controlled Clinical Trial with Fluphenazine Decanoate System/Organ Class Haloperidol decanoate (n=36) % Fluphenazine decanoate (n=36) % Gastrointestinal Disorders Nervous System Disorders a a Additional Adverse Reactions Reported in Double-Blind, Comparator, Open-Label and Dose-Response Clinical Trials Cardiac Disorders: Endocrine Disorders: Eye Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Investigations: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Reproductive System and Breast Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Psychiatric Disorders: Reproductive System and Breast Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders: The following adverse reactions relating to the active moiety haloperidol have been identified during postapproval use of haloperidol or haloperidol decanoate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Cardiac Disorders: Endocrine Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Hepatobiliary Disorders: Immune System Disorders: Investigations: Metabolic and Nutritional Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Pregnancy, Puerperium and Perinatal Conditions: Psychiatric Disorders: Renal and Urinary Disorders: Reproductive System and Breast Disorders: Respiratory, Thoracic and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-9994 or FDA at 1-800-FDA-1088 or www. gov/medwatch.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice. Table 1: Adverse Reactions Reported by >=1% of Haloperidol Decanoate-Treated Patients in a Double-Blind Active Comparator-Controlled Clinical Trial with Fluphenazine Decanoate System/Organ Class Haloperidol decanoate (n=36) % Fluphenazine decanoate (n=36) % Gastrointestinal Disorders Nervous System Disorders a a Additional Adverse Reactions Reported in Double-Blind, Comparator, Open-Label and Dose-Response Clinical Trials Cardiac Disorders: Endocrine Disorders: Eye Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Investigations: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Reproductive System and Breast Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Psychiatric Disorders: Reproductive System and Breast Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders:
Postmarketing Experience
The following adverse reactions relating to the active moiety haloperidol have been identified during postapproval use of haloperidol or haloperidol decanoate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Cardiac Disorders: Endocrine Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Hepatobiliary Disorders: Immune System Disorders: Investigations: Metabolic and Nutritional Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Pregnancy, Puerperium and Perinatal Conditions: Psychiatric Disorders: Renal and Urinary Disorders: Reproductive System and Breast Disorders: Respiratory, Thoracic and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-9994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Since the pharmacologic and clinical actions of haloperidol decanoate injection, 50 mg/mL and 100 mg/mL are attributed to haloperidol as the active medication, Contraindications, Warnings, and additional information are those of haloperidol, modified only to reflect the prolonged action. WARNINGS Hypersensitivity Reactions ADVERSE REACTIONS WARNINGS, Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy Bodies WARNINGS, Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy Bodies

Usage in Pregnancy
Rats or rabbits administered oral haloperidol at doses of 0.5 to 7.5 mg/kg, which are approximately 0.2 to 7 times the maximum recommended human dose (MRHD) of 20 mg/day based on mg/m 2 2 Non-Teratogenic Effects Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Haloperidol decanoate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol decanoate.
Pediatric Use
Safety and effectiveness of haloperidol decanoate in children have not been established.
Geriatric Use
Clinical studies of haloperidol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not consistently identified differences in responses between the elderly and younger patients. However, the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women (see WARNINGS Tardive Dyskinesia DOSAGE AND ADMINISTRATION
Use in Hepatic Impairment
Studies in patients with hepatic impairment have not been conducted. Haloperidol concentrations may increase in hepatically impaired patients, because it is primarily metabolized by the liver and protein binding may decrease.

Combined Use of Haloperidol and Lithium
An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and fasting blood sugar) followed by irreversible brain damage has occurred in a few patients treated with lithium plus haloperidol. A causal relationship between these events and the concomitant administration of lithium and haloperidol has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear.
Drug Interactions
Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using haloperidol in combination with other drugs have been evaluated as described below. Pharmacodynamic Interactions WARNINGS Cardiovascular Effects Caution is advised when haloperidol decanoate is used in combination with drugs known to cause electrolyte imbalance (e.g., diuretics or corticosteroids) because hypokalemia, hypomagnesemia, and hypocalcemia are risk factors for QT prolongation. As with other antipsychotic agents, it should be noted that haloperidol may be capable of potentiating CNS depressants such as anesthetics, opioids, and alcohol. Pharmacokinetic Interactions Drugs that May Increase Haloperidol Plasma Concentrations Haloperidol is metabolized by several routes. 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 CYP2D6 enzyme may result in increased haloperidol concentrations. The effect of CYP3A4 inhibition and of decreased CYP2D6 enzyme may be additive. The haloperidol plasma concentrations increased when a CYP3A4 and/or CYP2D6 inhibitor was coadministered with haloperidol. Examples include: CYP3A4 inhibitors en dash alprazolam; itraconazole, ketoconazole, nefazodone, ritonavir. Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTc interval prolongation (see WARNINGS Cardiovascular Effects 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 haloperidol decanoate dose be decreased as deemed necessary. Valproate: Drugs that May Decrease Haloperidol Plasma Concentrations Hypericum, perforatum Rifampin: Carbamazepine: During combination treatment with inducers of CYP3A4, it is recommended that patients be monitored and the haloperidol decanoate 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 haloperidol decanoate, or adjust the dosage interval. Effect of Haloperidol on Other Drugs

WARNINGS
Increased Mortality in Elderly Patients with D ementia-Related Psychosis BOXED WARNING Cases of sudden death, QTc interval-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol (see ADVERSE REACTIONS DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY. Tachycardia and hypotension (including orthostatic hypotension) have also been reported in occasional patients (see ADVERSE REACTIONS In controlled trials, elderly patients with dementia-related psychosis treated with some antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e. , stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for haloperidol decanoate injection, other antipsychotics, or other patient populations. Haloperidol decanoate injection should be used with caution in patients with risk factors for cerebrovascular adverse reactions. A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs (see ADVERSE REACTIONS not A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs (see ADVERSE REACTIONS Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity with haloperidol treatment include severe extrapyramidal symptoms, confusion, sedation, and falls. In addition, haloperidol may impair the antiparkinson effects of levodopa and other dopamine agonists. Haloperidol decanoate is contraindicated in patients with Parkinson’s Disease or Dementia with Lewy Bodies (see CONTRAINDICATIONS There have been postmarketing reports of hypersensitivity reactions with haloperidol. These include anaphylactic reaction, angioedema, dermatitis exfoliative, hypersensitivity vasculitis, rash, urticaria, face edema, laryngeal edema, bronchospasm, and laryngospasm (see ADVERSE REACTIONS CONTRAINDICATIONS Motor instability, somnolence, and orthostatic hypotension have been reported with the use of antipsychotics, including haloperidol decanoate, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently during treatment. An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and fasting blood sugar) followed by irreversible brain damage has occurred in a few patients treated with lithium plus haloperidol. A causal relationship between these events and the concomitant administration of lithium and haloperidol has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including haloperidol. It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly.
Other
Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL should be administered cautiously to patients:
Carcinogenesis,Mutagenesis, and Impairment of Fertility
No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella assay. Negative or inconsistent positive findings have been obtained in in vitro in vivo 2 2 in vitro
OVERDOSAGE
While overdosage is less likely to occur with a parenteral than with an oral medication, information pertaining to haloperidol is presented, modified only to reflect the extended duration of action of haloperidol decanoate. In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor, as demonstrated by the akinetic or agitans types, respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. ADVERSE REACTIONS Since there is no specific antidote, treatment is primarily supportive. Dialysis is not recommended in the treatment of overdose because it removes only very small amounts of haloperidol. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine must not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks, and then withdrawn gradually as extrapyramidal symptoms may emerge. ECG and vital signs should be monitored especially for signs of QTc-interval prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222).
Manifestations
In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor, as demonstrated by the akinetic or agitans types, respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered. ADVERSE REACTIONS
Treatment
Since there is no specific antidote, treatment is primarily supportive. Dialysis is not recommended in the treatment of overdose because it removes only very small amounts of haloperidol. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine must not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks, and then withdrawn gradually as extrapyramidal symptoms may emerge. ECG and vital signs should be monitored especially for signs of QTc-interval prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222).

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