Haldol Decanoate - Haloperidol Decanoate injection prescribing information
WARNING
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
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 is not clear. HALDOL decanoate is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS ).
INDICATIONS AND USAGE
HALDOL decanoate 50 and HALDOL decanoate 100 are indicated for the treatment of patients with schizophrenia who require prolonged parenteral antipsychotic therapy.
DOSAGE AND ADMINISTRATION
HALDOL decanoate 50 and HALDOL decanoate 100 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.
HALDOL decanoate 50 and HALDOL decanoate 100 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 HALDOL (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 HALDOL decanoate 50 or HALDOL decanoate 100 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.
Initial Therapy
Conversion from oral haloperidol to haloperidol decanoate can be achieved by using an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose in oral haloperidol equivalents.
In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion.
In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections.
The initial dose of haloperidol decanoate should not exceed 100 mg regardless of previous antipsychotic dose requirements. If, therefore, conversion requires more than 100 mg of haloperidol decanoate as an initial dose, that dose should be administered in two injections, i.e. a maximum of 100 mg initially followed by the balance in 3 to 7 days.
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 patient.
| Monthly | ||
|---|---|---|
| Patients | 1 st Month | Maintenance |
| Stabilized on low daily oral doses (up to 10 mg/day) | 10–15 × Daily Oral Dose | 10–15 × Previous Daily Oral Dose |
| Elderly or Debilitated | ||
| High dose Risk of relapse | 20 × Daily Oral Dose | 10–15 × Previous Daily Oral Dose |
| Tolerant to oral haloperidol | ||
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.
CONTRAINDICATIONS
Since the pharmacologic and clinical actions of HALDOL decanoate 50 and HALDOL decanoate 100 are attributed to HALDOL (haloperidol) as the active medication, Contraindications, Warnings, and additional information are those of HALDOL, modified only to reflect the prolonged action.
HALDOL 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 (see WARNINGS, Hypersensitivity Reactions and ADVERSE REACTIONS ).
- Parkinson's disease (see WARNINGS, Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies ).
- Dementia with Lewy bodies (see WARNINGS, Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies ).
ADVERSE REACTIONS
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 HALDOL and Lithium
- WARNINGS, General
- PRECAUTIONS, Leukopenia, Neutropenia, and Agranulocytosis
- PRECAUTIONS, Other
- PRECAUTIONS, Usage in Pregnancy
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.
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.
| System/Organ Class Adverse Reaction | Haloperidol decanoate (n=36) % | Fluphenazine decanoate (n=36) % |
|---|---|---|
| Gastrointestinal Disorders | ||
| Abdominal pain | 2.8 | 0 |
| Nervous System Disorders | ||
| Extrapyramidal disorder Precise 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: Tachycardia
Endocrine Disorders: Hyperprolactinemia
Eye Disorders: Vision blurred
Gastrointestinal Disorders: Constipation, Dry mouth, Salivary hypersecretion
General Disorders and Administration Site Conditions: Injection site reaction
Investigations: Weight increased
Musculoskeletal and Connective Tissue Disorders: Muscle rigidity
Nervous System Disorders: Dyskinesia, Dystonia, Cogwheel rigidity, Hypertonia, Masked Facies, Sedation, Somnolence
Reproductive System and Breast Disorders: Erectile dysfunction
Adverse 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 twitching
Nervous System Disorders: Neuroleptic malignant syndrome, Tardive dyskinesia, Bradykinesia, Hyperkinesia, Hypokinesia, Dizziness, Nystagmus
Psychiatric Disorders: Loss of libido, Restlessness
Reproductive System and Breast Disorders: Amenorrhea, Galactorrhea, Dysmenorrhea, Menorrhagia, Breast discomfort
Skin and Subcutaneous Tissue Disorders: Acneiform skin reactions
Vascular Disorders: Hypotension, Orthostatic hypotension
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: Pancytopenia, Agranulocytosis, Thrombocytopenia, Leukopenia, Neutropenia
Cardiac Disorders: Ventricular fibrillation, Torsade de pointes, Ventricular tachycardia, Extrasystoles
Endocrine Disorders: Inappropriate antidiuretic hormone secretion
Gastrointestinal Disorders: Vomiting, Nausea
General Disorders and Administration Site Conditions: Sudden death, Face edema, Edema, Hyperthermia, Hypothermia, Injection site abscess
Hepatobiliary Disorders: Acute hepatic failure, Hepatitis, Cholestasis, Jaundice, Liver function test abnormal
Immune System Disorders: Anaphylactic reaction, Hypersensitivity
Investigations: Electrocardiogram QT prolonged, Weight decreased
Metabolic and Nutritional Disorders: Hypoglycemia
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis
Nervous System Disorders: Convulsion, Opisthotonus, Tardive dystonia
Pregnancy, Puerperium and Perinatal Conditions: Drug withdrawal syndrome neonatal
Psychiatric Disorders: Agitation, Confusional state, Depression, Insomnia
Renal and Urinary Disorders: Urinary retention
Reproductive System and Breast Disorders: Priapism, Gynecomastia
Respiratory, Thoracic and Mediastinal Disorders: Laryngeal edema, Bronchospasm, Laryngospasm, Dyspnea
Skin and Subcutaneous Tissue Disorders: Angioedema, Dermatitis exfoliative, Hypersensitivity vasculitis, Photosensitivity reaction, Urticaria, Pruritus, Rash, Hyperhidrosis
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
Since QTc interval-prolongation has been observed during HALDOL treatment, caution is advised when prescribing to a patient with QT-prolongation conditions or to patients receiving medications known to prolong the QTc-interval (see WARNINGS, Cardiovascular Effects ). Examples include (but are not limited to): Class 1A antiarrhythmics (e.g., procainamide, quinidine, disopyramide); Class 3 antiarrhythmics (e.g., amiodarone, sotalol); and other drugs such as citalopram, erythromycin, levofloxacin, methadone, and ziprasidone.
Caution is advised when HALDOL 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 – alprazolam; itraconazole, ketoconazole, nefazodone, ritonavir.
- CYP2D6 inhibitors – chlorpromazine; promethazine; quinidine; paroxetine, sertraline, venlafaxine.
- Combined CYP3A4 and CYP2D6 inhibitors – fluoxetine, fluvoxamine; ritonavir.
- Buspirone.
Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTc interval prolongation (see WARNINGS – Cardiovascular Effects ). 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 decanoate dose be decreased as deemed necessary.Valproate: 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 include (but are not limited to): carbamazepine, phenobarbital, phenytoin, rifampin, St John's Wort ( Hypericum, perforatum ).
Rifampin
In a study of 12 patients with schizophrenia coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other patients with schizophrenia treated with oral haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations.
Carbamazepine
In a study in 11 patients with schizophrenia coadministered haloperidol and increasing doses of carbamazepine, haloperidol plasma concentrations decreased linearly with increasing carbamazepine concentrations.
During combination treatment with inducers of CYP3A4, it is recommended that patients be monitored and the HALDOL 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 HALDOL decanoate, or adjust the dosage interval.
Effect of Haloperidol on Other Drugs
Haloperidol is an inhibitor of CYP2D6. Plasma concentrations of CYP2D6 substrates (e,g. tricyclic antidepressants such as desipramine or imipramine) may increase when they are co-administered with haloperidol.
DESCRIPTION
Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL (haloperidol). It has a markedly extended duration of effect. It is available in sesame oil in sterile form for intramuscular (IM) injection. The structural formula of haloperidol decanoate, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate, is:
Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in most organic solvents.
Each mL of HALDOL decanoate 50 for IM injection contains 50 mg haloperidol (present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative.
Each mL of HALDOL decanoate 100 for IM injection contains 100 mg haloperidol (present as haloperidol decanoate 141.04 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative.
CLINICAL PHARMACOLOGY
HALDOL decanoate 50 and HALDOL decanoate 100 are the long-acting forms of HALDOL (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 ) receptors.
Administration of haloperidol decanoate in sesame oil results in slow and sustained release of haloperidol. The plasma concentrations of haloperidol gradually rise, reaching a peak at about 6 days after the injection, and falling thereafter, with an apparent half-life of about 3 weeks. Steady state plasma concentrations are achieved within 2 to 4 months in patient receiving monthly injections. The relationship between dose of haloperidol decanoate and plasma haloperidol concentration is roughly linear for doses below 450 mg. It should be noted, however, that the pharmacokinetics of haloperidol decanoate following intramuscular injections can be quite variable between subjects.
HOW SUPPLIED
HALDOL (haloperidol) decanoate 50 for IM injection, 50 mg haloperidol as 70.52 mg per mL haloperidol decanoate:
NDC 50458-253-03 3 × 1 mL ampules.
HALDOL (haloperidol) decanoate 100 for IM injection, 100 mg haloperidol as 141.04 mg per mL haloperidol decanoate:
NDC 50458-254-14, 5 × 1 mL ampules.
Store at controlled room temperature (15°–30° C, 59°–86° F). Do not refrigerate or freeze.
Protect from light.
Keep out of reach of children.
