Haloperidol Decanoate Prescribing Information
Cases of sudden death, QTc interval-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol (see
Tachycardia and hypotension (including orthostatic hypotension) have also been reported in occasional patients (see
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, other antipsychotics, or other patient populations. Haloperidol decanoate 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
Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
Tardive dyskinesia, may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs (see
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with haloperidol.
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
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
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.
Although not reported with haloperidol, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs.
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 and 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.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients must be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate. Furthermore, it is recommended that patients being considered for haloperidol decanoate therapy have been treated with, and tolerate well, short-acting haloperidol in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting forms of haloperidol.
The dose of haloperidol decanoate injection, 50 mg/mL or haloperidol decanoate injection, 100 mg/mL should be expressed in terms of its haloperidol content. The starting dose of haloperidol decanoate should be based on the patient’s age, clinical history, physical condition, and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed. For patients previously maintained on low doses of antipsychotics (e.g., up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate be 10 - 15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate.
Since the pharmacologic and clinical actions of haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 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.
Haloperidol is contraindicated in patients with:
• Severe toxic central nervous system depression or comatose states from any cause.• Hypersensitivity to this drug – hypersensitivity reactions have included anaphylactic reaction and angioedema (seeandHypersensitivity ReactionsThere 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). Haloperidol decanoate is contraindicated in patients with hypersensitivity to this drug (seeCONTRAINDICATIONS).).ADVERSE REACTIONSThe following adverse reactions are discussed in more detail in other sections of the labeling:
• WARNINGS, Increased Mortality in Elderly Patients with Dementia-Related Psychosis• WARNINGS, Cardiovascular Effects• WARNINGS, Tardive Dyskinesia• WARNINGS, Neuroleptic Malignant Syndrome• WARNINGS, Hypersensitivity Reactions• WARNINGS, Falls• WARNINGS, Combined Use of Haloperidol and Lithium• WARNINGS, General• PRECAUTIONS, Leukopenia, Neutropenia, and Agranulocytosis• PRECAUTIONS, Other• PRECAUTIONS, Usage in Pregnancy
Clinical Trials ExperienceBecause 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.
The data described below reflect exposure to haloperidol in 410 patients who participated in 13 clinical trials with haloperidol decanoate (15 to 500 mg/month) in the treatment of schizophrenia or schizoaffective disorder. These clinical trials comprised:
• 1 double-blind, active comparator-controlled trial with fluphenazine decanoate.• 2 trials comparing the decanoate formulation to oral haloperidol.• 9 open-label trials.• 1 dose-response trial.
The most common adverse reactions in haloperidol decanoate-treated patients in the double-blind, active comparator-controlled clinical trial with fluphenazine decanoate (≥5%) were: Parkinsonism, and oculogyric crisis.
Adverse Reactions Reported at ≥1% Incidence in a Double-Blind Active Comparator-Controlled Clinical Trial
Adverse reactions occurring in ≥1% of haloperidol decanoate-treated patients in a double-blind, clinical trial with the active comparator fluphenazine decanoate are shown in Table 1.
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 ClassAdverse Reaction
Haloperidol decanoate(n=36)%Fluphenazine decanoate(n=36)%Gastrointestinal DisordersAbdominal pain
2.8
0
Nervous System DisordersExtrapyramidal disorderPrecise incidence for extrapyramidal disorder cannot be determined; reporting rates of some individual symptoms of extrapyramidal disorder are lower for haloperidol decanoate than for the active comparator, but the terms are included here because the events are considered associated with the drug.:
Parkinsonism
30.6
44.4
Oculogyric crisis
5.6
0
Akinesia
2.8
22.2
Akathisia
2.8
13.9
Tremor
2.8
0
Headache
2.8
0
Additional Adverse Reactions Reported in Double-Blind, Comparator, Open-Label and Dose-Response Clinical Trials
Additional adverse reactions that are listed below were reported by haloperidol decanoate-treated patients in comparator, open-label, and dose-response clinical trials, or at <1% incidence in a double-blind, active comparator-controlled clinical trial with fluphenazine decanoate.
Cardiac Disorders:TachycardiaEndocrine Disorders:HyperprolactinemiaEye Disorders:Vision blurredGastrointestinal Disorders:Constipation, Dry mouth, Salivary hypersecretionGeneral Disorders and Administration Site Conditions:Injection site reactionInvestigations:Weight increasedMusculoskeletal and Connective Tissue Disorders:Muscle rigidityNervous System Disorders:Dyskinesia, Dystonia, Cogwheel rigidity, Hypertonia, Masked Facies, Sedation, SomnolenceReproductive System and Breast Disorders:Erectile dysfunctionAdverse Reactions Identified in Clinical Trials with Haloperidol (Non-Decanoate Formulations)
The adverse reactions listed below were identified with non-decanoate formulations, and reflect exposure to the active moiety haloperidol in the following:
• 284 patients who participated in 3 double-blind, placebo-controlled clinical trials with haloperidol (injection or oral formulation, 2 to 20 mg/day); two trials were in the treatment of schizophrenia and one in the treatment of bipolar disorder.• 1295 patients who participated in 16 double-blind, active comparator-controlled clinical trials with haloperidol (injection or oral formulation, 1 to 45 mg/day) in the treatment of schizophrenia.
Musculoskeletal and Connective Tissue Disorders:Torticollis, Trismus, Muscle twitchingNervous System Disorders:Neuroleptic malignant syndrome, Tardive dyskinesia, Bradykinesia, Hyperkinesia, Hypokinesia, Dizziness, NystagmusPsychiatric Disorders:Loss of libido, RestlessnessReproductive System and Breast Disorders:Amenorrhea, Galactorrhea, Dysmenorrhea, Menorrhagia, Breast discomfortSkin and Subcutaneous Tissue Disorders:Acneiform skin reactionsVascular Disorders:Hypotension, Orthostatic hypotensionPostmarketing ExperienceThe 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:Pancytopenia, Agranulocytosis, Thrombocytopenia, Leukopenia, NeutropeniaCardiac Disorders:Ventricular fibrillation, Torsade de pointes, Ventricular tachycardia, ExtrasystolesEndocrine Disorders:Inappropriate antidiuretic hormone secretionGastrointestinal Disorders:Vomiting, NauseaGeneral Disorders and Administration Site Conditions:Sudden death, Face edema, Edema, Hyperthermia, Hypothermia, Injection site abscessHepatobiliary Disorders:Acute hepatic failure, Hepatitis, Cholestasis, Jaundice, Liver function test abnormalImmune System Disorders:Anaphylactic reaction, HypersensitivityInvestigations:Electrocardiogram QT prolonged, Weight decreasedMetabolic and Nutritional Disorders:HypoglycemiaMusculoskeletal and Connective Tissue Disorders:RhabdomyolysisNervous System Disorders:Convulsion, Opisthotonus, Tardive dystoniaPregnancy, Puerperium and Perinatal Conditions:Drug withdrawal syndrome neonatalPsychiatric Disorders:Agitation, Confusional state, Depression, InsomniaRenal and Urinary Disorders:Urinary retentionReproductive System and Breast Disorders:Priapism, GynecomastiaRespiratory, Thoracic and Mediastinal Disorders:Laryngeal edema, Bronchospasm, Laryngospasm, DyspneaSkin and Subcutaneous Tissue Disorders:Angioedema, Dermatitis exfoliative, Hypersensitivity vasculitis, Photosensitivity reaction, Urticaria, Pruritus, Rash, HyperhidrosisTo report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.• Parkinson’s disease (see).Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy BodiesPatients 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).• Dementia with Lewy bodies (see).Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy BodiesPatients 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).
The following adverse reactions are discussed in more detail in other sections of the labeling:
• WARNINGS, Increased Mortality in Elderly Patients with Dementia-Related Psychosis• WARNINGS, Cardiovascular Effects• WARNINGS, Tardive Dyskinesia• WARNINGS, Neuroleptic Malignant Syndrome• WARNINGS, Hypersensitivity Reactions• WARNINGS, Falls• WARNINGS, Combined Use of Haloperidol and Lithium• WARNINGS, General• PRECAUTIONS, Leukopenia, Neutropenia, and Agranulocytosis• PRECAUTIONS, Other• PRECAUTIONS, Usage in Pregnancy
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.