PRECAUTIONS SECTION.

PRECAUTIONS. Leukopenia, Neutropenia, and Agranulocytosis. Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including HALDOL decanoate. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with history of clinically significant low WBC or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of HALDOL decanoate should be considered at the first sign of clinically significant decline in WBC in the absence of other causative factors.Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm 3) should discontinue HALDOL decanoate and have their WBC followed until recovery. Other. HALDOL decanoate 50 and HALDOL decanoate 100 should be administered cautiously to patients:with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and vasopressor be required, epinephrine must not be used since HALDOL (haloperidol) may block its vasopressor activity, and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used.receiving anticonvulsant medications, with history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained.with known allergies, or with history of allergic reactions to drugs.receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione).Haloperidol may impair the antiparkinson effects of levodopa and other dopamine agonists. If concomitant antiparkinson medication is required, it may have to be continued after HALDOL decanoate 50 or HALDOL decanoate 100 is discontinued because of the prolonged action of haloperidol decanoate. If both drugs are discontinued simultaneously, extrapyramidal symptoms may occur. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with HALDOL Decanoate.When HALDOL decanoate is used to control mania in cyclic disorders, there may be rapid mood swing to depression.Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL.. with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and vasopressor be required, epinephrine must not be used since HALDOL (haloperidol) may block its vasopressor activity, and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used.. receiving anticonvulsant medications, with history of seizures, or with EEG abnormalities, because HALDOL may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained.. with known allergies, or with history of allergic reactions to drugs.. receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione).. Information for Patients. Haloperidol decanoate may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving motor vehicle. The ambulatory patient should be warned accordingly.The use of alcohol with this drug should be avoided due to possible additive effects and hypotension.. 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 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 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 lesser extent, CYP2D6. Inhibition of these routes of metabolism by another drug or 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 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 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, drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.. CYP3A4 inhibitors alprazolam; itraconazole, ketoconazole, nefazodone, ritonavir.. CYP2D6 inhibitors chlorpromazine; promethazine; quinidine; paroxetine, sertraline, venlafaxine.. Combined CYP3A4 and CYP2D6 inhibitors fluoxetine, fluvoxamine; ritonavir.. Buspirone.. 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 Johns Wort Hypericum, perforatum). Rifampin. In study of 12 patients with schizophrenia coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In other patients with schizophrenia treated with oral haloperidol and rifampin, discontinuation of rifampin produced mean 3.3-fold increase in haloperidol concentrations. Carbamazepine. In 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.. 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 and in vivo studies of effects of short-acting haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive at this time. Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to mg/kg daily for 18 months). In the rat study survival was reduced in all dose groups, decreasing the number of rats at risk for developing tumors. However, relatively greater number of rats survived to the end of the study in high-dose male and female groups, these animals did not have greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of haloperidol related increase in the incidence of neoplasia in rats at doses up to approximately 2.5 times the maximum recommended human dose (MRHD) of 20 mg/day based on mg/m body surface area. In female micethere was statistically significant increase in mammary gland neoplasia and total tumor incidence at doses approximately 0.3 and 1.2 times the MRHD based on mg/m body surface area and there was statistically significant increase in pituitary gland neoplasia at approximately 1.2 times the MRHD In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, factor of potential importance if the prescription of these drugs is contemplated in patient with previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.. 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 times the maximum recommended human dose (MRHD) of 20 mg/day based on mg/m body surface area. showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality. No fetal abnormalities were observed at these doses in rats or rabbits. Cleft palate has been observed in mice administered oral haloperidol at dose of 0.5 mg/kg, which is approximately 0.1 times the MRHD based on mg/m body surface area. There are no adequate and well-controlled studies in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of HALDOL along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established with these cases. Since such experience does not exclude the possibility of fetal damage due to HALDOL, haloperidol decanoate should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies potential risk to the fetus.. 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.HALDOL 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). Also, the pharmacokinetics of haloperidol in geriatric patients generally warrants the use of lower doses (see 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.

ADVERSE REACTIONS SECTION.

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 PsychosisWARNINGS, Cardiovascular EffectsWARNINGS, Tardive DyskinesiaWARNINGS, Neuroleptic Malignant Syndrome WARNINGS, Hypersensitivity ReactionsWARNINGS, FallsWARNINGS, Combined Use of HALDOL and LithiumWARNINGS, GeneralPRECAUTIONS, Leukopenia, Neutropenia, and AgranulocytosisPRECAUTIONS, OtherPRECAUTIONS, Usage in Pregnancy. 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 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.. double-blind, active comparator-controlled trial with fluphenazine decanoate.. trials comparing the decanoate formulation to oral haloperidol.. open-label trials.. dose-response trial.. Adverse Reactions Reported at >=1% Incidence in Double-Blind Active Comparator-Controlled Clinical Trial. Adverse reactions occurring in >=1% of haloperidol decanoate-treated patients in 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 Double-Blind Active Comparator-Controlled Clinical Trial with Fluphenazine Decanoate System/Organ Class Adverse Reaction Haloperidol decanoate (n=36) Fluphenazine decanoate (n=36) Gastrointestinal Disorders Abdominal pain2.80Nervous 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: Parkinsonism30.644.4 Oculogyric crisis5.60 Akinesia2.822.2 Akathisia2.813.9 Tremor2.80 Headache2.80. 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 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 double-blind, placebo-controlled clinical trials with haloperidol (injection or oral formulation, 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, 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 284 patients who participated in double-blind, placebo-controlled clinical trials with haloperidol (injection or oral formulation, 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, to 45 mg/day) in the treatment of schizophrenia.. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. HALDOL decanoate 50 and HALDOL decanoate 100 should be administered by deep intramuscular injection. 21 gauge needle is recommended. The maximum volume per injection site should not exceed 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 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 patients 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), 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 low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in 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. maximum of 100 mg initially followed by the balance in to 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.HALDOL DECANOATE DOSING RECOMMENDATIONSMonthlyPatients1 st Month MaintenanceStabilized on low daily oral doses (up to 10 mg/day) 10-15 Daily Oral Dose10-15 Previous Daily Oral DoseElderly or DebilitatedHigh dose Risk of relapse 20 Daily Oral Dose10-15 Previous Daily Oral DoseTolerant to oral haloperidolClose clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy. Haloperidol decanoate is usually administered monthly or every weeks. However, variation in patient response may dictate 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.

DRUG INTERACTIONS SECTION.

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 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 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 lesser extent, CYP2D6. Inhibition of these routes of metabolism by another drug or 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 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 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, drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.. CYP3A4 inhibitors alprazolam; itraconazole, ketoconazole, nefazodone, ritonavir.. CYP2D6 inhibitors chlorpromazine; promethazine; quinidine; paroxetine, sertraline, venlafaxine.. Combined CYP3A4 and CYP2D6 inhibitors fluoxetine, fluvoxamine; ritonavir.. Buspirone.. 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 Johns Wort Hypericum, perforatum). Rifampin. In study of 12 patients with schizophrenia coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In other patients with schizophrenia treated with oral haloperidol and rifampin, discontinuation of rifampin produced mean 3.3-fold increase in haloperidol concentrations. Carbamazepine. In 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.

WARNINGS SECTION.

WARNINGS. 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. HALDOL decanoate is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING). Cardiovascular Effects. Cases of sudden death, QTc interval-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol (see ADVERSE REACTIONS). Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with higher risk of QTc interval-prolongation and Torsades de Pointes. Also, QTc interval that exceeds 500 msec is associated with an increased risk of Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QTc-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QTc, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY. Tachycardia and hypotension (including orthostatic hypotension) have also been reported in occasional patients (see ADVERSE REACTIONS). 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 HALDOL decanoate, other antipsychotics, or other patient populations. HALDOL decanoate should be used with caution in patients with risk factors for cerebrovascular adverse reactions.. Tardive Dyskinesia. syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs (see ADVERSE REACTIONS). Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. 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 manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.. Neuroleptic Malignant Syndrome (NMS). potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs (see ADVERSE REACTIONS). Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at 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 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 HALDOL.. Neurological Adverse Reactions in Patients with Parkinsons Disease or Dementia with Lewy Bodies. Patients with Parkinsons 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. HALDOL decanoate is contraindicated in patients with Parkinsons Disease or Dementia with Lewy Bodies (see CONTRAINDICATIONS). Hypersensitivity Reactions. 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). HALDOL decanoate is contraindicated in patients with hypersensitivity to this drug (see CONTRAINDICATIONS). Falls. Motor instability, somnolence, and orthostatic hypotension have been reported with the use of antipsychotics, including HALDOL 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.. Combined Use of HALDOL 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 few patients treated with lithium plus HALDOL. causal relationship between these events and the concomitant administration of lithium and HALDOL 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.. General. number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including HALDOL (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 HALDOL, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Adverse Reactions Identified in Clinical Trials with HALDOL DECANOATEThe data described below reflect exposure to 15 mg to 500 mg (1.7 times the maximum recommended dosage) of HALDOL DECANOATE monthly in 13 clinical trials of 410 adult patients with schizophrenia or an unapproved condition. These clinical trials comprised of:1 double-blind, active comparator-controlled trial with fluphenazine decanoate (Trial 1).2 trials comparing HALDOL DECANOATE to oral haloperidol (Trials and 3).9 open-label trials.1 dose-response trial.The most common adverse reactions that occurred in >=5% of HALDOL DECANOATE-treated patients in Trial were Parkinsonism and oculogyric crisis.Adverse reactions that occurred in >=1% of HALDOL DECANOATE-treated patients in Trial are shown in Table 2. Trial was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the HALDOL DECANOATE and fluphenazine decanoate treatment groups.Table 2: Adverse Reactions that Occurred in >=1% of HALDOL DECANOATE-treated Patients and Fluphenazine Decanoate-treated Patients in Trial The study was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the HALDOL DECANOATE and the fluphenazine decanoate treatment groups. HALDOL DECANOATE (n=36) Fluphenazine decanoate (n=36) Extrapyramidal disorder: Parkinsonism31%44% Oculogyric crisis6%0% Akinesia3%22% Akathisia3%14% Tremor3%0%Abdominal pain3%0%Headache3%0%Less common adverse reactions (<1%) that occurred in Trial and other adverse reactions that occurred in Trials and 3, and open-label and dose-response clinical trials of HALDOL DECANOATE are listed below.Cardiac Disorders:Tachycardia Endocrine Disorders:Hyperprolactinemia Eye Disorders:Vision blurred Gastrointestinal Disorders:Constipation, Dry mouth, Salivary hypersecretion General Disorders and Administration Site Conditions:Weight increased, Injection site reaction Musculoskeletal and Connective Tissue Disorders:Muscle rigidity Nervous System Disorders:Dyskinesia, Dystonia, Cogwheel rigidity, Hypertonia, Masked facies, Sedation, Somnolence Reproductive System Disorders:Erectile dysfunction Adverse Reactions Identified in Clinical Trials with Immediate-Release Haloperidol ProductsBased on clinical trials with immediate-release haloperidol products that included 1,579 patients, the following adverse reactions were reported: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 1 double-blind, active comparator-controlled trial with fluphenazine decanoate (Trial 1).. trials comparing HALDOL DECANOATE to oral haloperidol (Trials and 3).. open-label trials.. dose-response trial.. Cardiac Disorders:Tachycardia Endocrine Disorders:Hyperprolactinemia Eye Disorders:Vision blurred Gastrointestinal Disorders:Constipation, Dry mouth, Salivary hypersecretion General Disorders and Administration Site Conditions:Weight increased, Injection site reaction Musculoskeletal and Connective Tissue Disorders:Muscle rigidity Nervous System Disorders:Dyskinesia, Dystonia, Cogwheel rigidity, Hypertonia, Masked facies, Sedation, Somnolence Reproductive System Disorders:Erectile dysfunction 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility. CarcinogenesisCarcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed at up to mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to mg/kg daily for 18 months).In the rat study, survival was reduced in all haloperidol dose groups, decreasing the number of rats at risk for developing tumors. However, relatively greater number of rats survived to the end of the study in the high dose haloperidol male and female groups. These haloperidol-treated rats at doses up to approximately 2.5 times the maximum recommended human oral dose (MRHD) of haloperidol of 20 mg/day based on mg/m 2body surface area did not have greater incidence of tumors than control-treated rats. In female mice, there was statistically significant increase in mammary gland neoplasia and total tumor incidence at haloperidol doses approximately 0.3 and 1.2 times the oral MRHD based on mg/m 2body surface area and there was statistically significant increase in pituitary gland neoplasia at approximately 1.2 times the oral MRHD. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, factor of potential importance if the prescription of these drugs is contemplated in patient with previously detected breast cancer. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs [see Warnings and Precautions (5.14)] MutagenesisNo mutagenic potential of haloperidol decanoate was found in the Ames Salmonella assay. Negative or inconsistent positive findings have been obtained in in vitroand in vivostudies of effects of haloperidol on chromosome structure and number. The available cytogenetic evidence is considered too inconsistent to be conclusive. Impairment of FertilityHaloperidol was orally administered to male rats at doses of 0.5, 2.5, and 15 mg/kg/day (approximately 0.2 to times the oral MRHD based on mg/m 2body surface area) for 63 days prior to mating with untreated females. Decreases in mating performance and fertility, as well as markedly decreased motor activity, was observed at seven times the oral MRHD based on mg/m 2body surface area. The NOAEL of 2.5 mg/kg/day is approximately equal to the oral MRHD based on mg/m 2body surface area. In the rat study, survival was reduced in all haloperidol dose groups, decreasing the number of rats at risk for developing tumors. However, relatively greater number of rats survived to the end of the study in the high dose haloperidol male and female groups. These haloperidol-treated rats at doses up to approximately 2.5 times the maximum recommended human oral dose (MRHD) of haloperidol of 20 mg/day based on mg/m 2body surface area did not have greater incidence of tumors than control-treated rats. In female mice, there was statistically significant increase in mammary gland neoplasia and total tumor incidence at haloperidol doses approximately 0.3 and 1.2 times the oral MRHD based on mg/m 2body surface area and there was statistically significant increase in pituitary gland neoplasia at approximately 1.2 times the oral MRHD. In male mice, no statistically significant differences in incidences of total tumors or specific tumor types were noted.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe plasma concentrations of haloperidol gradually rise, reaching peak at about days after the HALDOL DECANOATE injection, and fall thereafter, with an apparent half-life of about weeks. Steady state plasma concentrations of haloperidol are achieved within to months in patients receiving monthly HALDOL DECANOATE injections. The relationship between the HALDOL DECANOATE dosage and plasma haloperidol concentration is roughly linear for dosages below 450 mg (1.5 times the maximum recommended dosage [see Dosage and Administration (2.1)] however, the pharmacokinetics of haloperidol following intramuscular injections can be quite variable between patients. EliminationMetabolism: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 lesser extent, CYP2D6. Excretion:Less than 3% of administered haloperidol is eliminated unchanged in the urine. The apparent half-life of haloperidol following intramuscular injection of HALDOL DECANOATE is about weeks.Specific PopulationsPatients with Hepatic ImpairmentStudies in patients with hepatic impairment have not been conducted. Haloperidol is extensively metabolized in the liver, therefore, haloperidol concentrations may be higher in patients with hepatic impairment compared to patients with normal hepatic function [see Use in Specific Populations (8.6)]. Geriatric PatientsHaloperidol plasma concentrations in geriatric patients were higher than in younger adult patients when administered the same dosage. Results from small clinical studies suggest lower clearance and longer elimination half-life of haloperidol in geriatric patients. The results are within the observed variability in haloperidol pharmacokinetics [see Use in Specific Populations (8.5)] Patients with Renal ImpairmentStudies in patients with renal impairment have not been conducted.Drug Interaction StudiesKetoconazole and ParoxetineThe haloperidol plasma concentrations increased when ketoconazole (400 mg/day, strong CYP3A4 inhibitor) and paroxetine (20 mg/day, strong CYP2D6 inhibitor) were concomitantly administered with haloperidol [see Drug Interactions (7.2)] Valproate:Sodium valproate, drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations. Rifampin:In study with 12 patients with schizophrenia, concomitant administration of oral haloperidol and rifampin, strong CYP3A4 inducer, resulted in decreased plasma haloperidol concentrations by mean of 70% and increased mean scores on the Brief Psychiatric Rating Scale from baseline. In five other patients with schizophrenia treated with oral haloperidol and rifampin, discontinuation of rifampin resulted in mean 3.3-fold increase in haloperidol concentrations [see Drug Interactions (7.2)] Carbamazepine:In study with 11 patients with schizophrenia, concomitant administration of haloperidol and increasing doses of carbamazepine, CYP3A4 strong inducer, resulted in decreased haloperidol plasma concentrations in linear manner with increasing carbamazepine concentrations [see Drug Interactions (7.2)]. Effect of Haloperidol on Other DrugsHaloperidol is an inhibitor of CYP2D6. Plasma concentrations of CYP2D6 substrates may increase when they are concomitantly administered with haloperidol [see Drug Interactions (7.2)].

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of haloperidol, including HALDOL DECANOATE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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, QTc interval prolongation 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, Weight decreased Hepatobiliary Disorders:Acute hepatic failure, Hepatitis, Cholestasis, Jaundice, Liver function test abnormal Immune System Disorders:Anaphylactic reaction, Hypersensitivity Metabolic and Nutritional Disorders:Hypoglycemia Musculoskeletal and Connective Tissue Disorders:Rhabdomyolysis Nervous System Disorders:Convulsion, Opisthotonus, Tardive dystonia Pregnancy, Puerperium and Perinatal Conditions:Neonatal drug withdrawal syndrome 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 Blood and Lymphatic System Disorders:Pancytopenia, Agranulocytosis, Thrombocytopenia, Leukopenia, Neutropenia Cardiac Disorders:Ventricular fibrillation, Torsade de pointes, Ventricular tachycardia, Extrasystoles, QTc interval prolongation 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, Weight decreased Hepatobiliary Disorders:Acute hepatic failure, Hepatitis, Cholestasis, Jaundice, Liver function test abnormal Immune System Disorders:Anaphylactic reaction, Hypersensitivity Metabolic and Nutritional Disorders:Hypoglycemia Musculoskeletal and Connective Tissue Disorders:Rhabdomyolysis Nervous System Disorders:Convulsion, Opisthotonus, Tardive dystonia Pregnancy, Puerperium and Perinatal Conditions:Neonatal drug withdrawal syndrome 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy:Neonates exposed to HALDOL DECANOATE during the third trimester of pregnancy may develop extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and decreased feeding) 8.1). Lactation:Monitor breastfed infants for excessive sedation, irritability, poor feeding, abnormal muscle movements, and tremors 8.2). Pregnancy:Neonates exposed to HALDOL DECANOATE during the third trimester of pregnancy may develop extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and decreased feeding) 8.1). Lactation:Monitor breastfed infants for excessive sedation, irritability, poor feeding, abnormal muscle movements, and tremors 8.2). 8.1 Pregnancy. Risk SummaryAvailable data from published epidemiologic studies of pregnant patients exposed to haloperidol have not established drug-associated risk of major birth defects or miscarriage. Case reports of limb malformations in neonates have been reported in haloperidol-treated mothers; however, causal relationships were not established in these cases. There are risks to the pregnant patient from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide (see Clinical Considerations) HALDOL DECANOATE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and decreased feeding) following delivery (see Clinical Considerations) The estimated background risk of major birth defects and miscarriage in patients with schizophrenia is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-associated Maternal and/or Embryo/Fetal Risk:There is risk to the pregnant patient from untreated schizophrenia, including increased risk of schizophrenia relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions:Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and decreased feeding have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. Transient neonatal dyskinesia has also been reported. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal, withdrawal, and dyskinesia symptoms and manage symptoms appropriately. DataAnimal Data:Rats or rabbits administered oral haloperidol at doses of 0.5 to 7.5 mg/kg (approximately 0.2 to times the maximum recommended human oral dose (MRHD) of 20 mg/day based on mg/m 2body surface area) showed an increase in incidence of resorption, reduced fertility, delayed delivery, and pup mortality. No fetal abnormalities were observed at these doses in rats or rabbits. Cleft palate has been observed in mice administered oral haloperidol at dose of 0.5 mg/kg, which is approximately 0.1 times the oral MRHD based on mg/m 2body surface area. 8.2 Lactation. Risk SummaryLiterature reports suggest that haloperidol is detected in human milk of haloperidol-treated mothers with relative infant dose ranging from 2% to 12%. Haloperidol has also been detected in the plasma and urine of breastfed infants. There has been report of lethargy, poor feeding, and slowing of motor movements in an infant exposed to haloperidol through human milk. Haloperidol may increase prolactin levels in some patients which can lead to galactorrhea.Monitor infants exposed to HALDOL DECANOATE via human milk for excessive sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for HALDOL DECANOATE and any potential adverse effects on the breastfed child from HALDOL DECANOATE or from the mothers underlying condition.. 8.3 Females and Males of Reproductive Potential. InfertilityFemales:Based on the pharmacologic action of haloperidol (D2 receptor antagonism), treatment with HALDOL DECANOATE may result in an increase in serum prolactin levels, which may lead to reduction in fertility in females of reproductive potential. Males:Based on animal studies, male fertility may be impaired by treatment with haloperidol [see Nonclinical Toxicology (13.1)] . 8.4 Pediatric Use. Safety and effectiveness of HALDOL DECANOATE have not been established in pediatric patients.. 8.5 Geriatric Use. Clinical studies of HALDOL DECANOATE did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.The exposure of haloperidol may be higher in geriatric patients compared to young adult patients. Results from small clinical studies suggest lower clearance and longer elimination half-life of haloperidol in geriatric patients [see Clinical Pharmacology (12.3)]. Consider starting at the low end of the recommended dosing range for the first HALDOL DECANOATE dose in geriatric patients [see Dosage and Administration (2.1)] Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. HALDOL DECANOATE is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)] Elderly patients with dementia-related psychosis treated with antipsychotics had an increased risk of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) including fatalities, compared to those treated with placebo [see Warnings and Precautions (5.4)] Antipsychotic drugs increase the risk of tardive dyskinesia and this risk appears to be highest among the elderly, particularly elderly women [see Warnings and Precautions (5.5)] . 8.6 Hepatic Impairment. Haloperidol is extensively metabolized in the liver, therefore, haloperidol concentrations may be higher in patients with hepatic impairment compared to patients with normal hepatic function. In patients with hepatic impairment, consider starting at the low end of the recommended dosing range for the first HALDOL DECANOATE dose [see Dosage and Administration (2.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Sudden Death, Torsades de Pointes (TdP), and QTc Interval Prolongation:Avoid use of HALDOL DECANOATE in patients who are at risk of developing TdP. Avoid concomitant use of HALDOL DECANOATE with drugs that may increase risk of QTc interval prolongation or increase haloperidol exposure. Obtain ECG and serum electrolytes at baseline and during treatment as clinically indicated 5.2). Tachycardia and Hypotension:Monitor orthostatic vital signs 5.3). Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis:Use with caution in patients with schizophrenia who have risk factors for cerebrovascular adverse reactions 5.4). Tardive Dyskinesia:Discontinue treatment if clinically appropriate 5.5). Neuroleptic Malignant Syndrome (NMS):Immediately discontinue and monitor closely 5.6). Seizures:HALDOL DECANOATE is generally not recommended in patients receiving antiseizure drugs or who have history of seizures or EEG abnormalities. If clinically, indicated, maintain patients taking HALDOL DECANOATE on adequate antiseizure therapy 5.8). Potential for Cognitive and Motor Impairment:Advise patients to not drive motor vehicle or operate hazardous machinery until they are reasonably certain HALDOL DECANOATE does not impair their cognitive and motor functions 5.11). Risk of Encephalopathic Syndrome with Concomitant Use of Lithium:Monitor closely for early signs of neurological toxicity and discontinue HALDOL DECANOATE if such signs appear 5.12). Leukopenia, Neutropenia, and Agranulocytosis:Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing HALDOL DECANOATE if clinically significant decline in WBC occurs in absence of other causative factors. Discontinue HALDOL DECANOATE in patients with clinically significant neutropenia or an absolute neutrophile count of <1,000/mm 3( 5.13). Hyperprolactinemia:Elevated prolactin levels may occur during acute and chronic use 5.14). Sudden Death, Torsades de Pointes (TdP), and QTc Interval Prolongation:Avoid use of HALDOL DECANOATE in patients who are at risk of developing TdP. Avoid concomitant use of HALDOL DECANOATE with drugs that may increase risk of QTc interval prolongation or increase haloperidol exposure. Obtain ECG and serum electrolytes at baseline and during treatment as clinically indicated 5.2). Tachycardia and Hypotension:Monitor orthostatic vital signs 5.3). Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis:Use with caution in patients with schizophrenia who have risk factors for cerebrovascular adverse reactions 5.4). Tardive Dyskinesia:Discontinue treatment if clinically appropriate 5.5). Neuroleptic Malignant Syndrome (NMS):Immediately discontinue and monitor closely 5.6). Seizures:HALDOL DECANOATE is generally not recommended in patients receiving antiseizure drugs or who have history of seizures or EEG abnormalities. If clinically, indicated, maintain patients taking HALDOL DECANOATE on adequate antiseizure therapy 5.8). Potential for Cognitive and Motor Impairment:Advise patients to not drive motor vehicle or operate hazardous machinery until they are reasonably certain HALDOL DECANOATE does not impair their cognitive and motor functions 5.11). Risk of Encephalopathic Syndrome with Concomitant Use of Lithium:Monitor closely for early signs of neurological toxicity and discontinue HALDOL DECANOATE if such signs appear 5.12). Leukopenia, Neutropenia, and Agranulocytosis:Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing HALDOL DECANOATE if clinically significant decline in WBC occurs in absence of other causative factors. Discontinue HALDOL DECANOATE in patients with clinically significant neutropenia or an absolute neutrophile count of <1,000/mm 3( 5.13). Hyperprolactinemia:Elevated prolactin levels may occur during acute and chronic use 5.14). 5.1 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. In an analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, the risk of death in antipsychotic drug-treated patients was 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of typical 10-week controlled trial, the incidence of death in antipsychotic drug-treated patients was about 4.5%, compared to an incidence of about 2.6% in placebo-treated patients. 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.HALDOL DECANOATE is not approved for the treatment of patients with dementia-related psychosis [see Indications and Usage (1)] . 5.2 Sudden Death, Torsades de Pointes, and QTc Interval Prolongation. Cases of sudden death, torsades de pointes (TdP) and QTc interval prolongation have been reported in haloperidol-treated patients [see Adverse Reactions (6.1, 6.2)] Cases have been reported even in the absence of predisposing factors. Higher than recommended haloperidol dosages were associated with higher risk of TdP and QTc interval prolongation. Avoid use of HALDOL DECANOATE in patients who are at significant risk of developing TdP including those with congenital long QT syndrome, uncontrolled or significant cardiac disease, recent myocardial infarction, ischemic cardiomyopathy, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Avoid the concomitant use of HALDOL DECANOATE with drugs that may increase the risk of the QTc interval prolongation or increase haloperidol exposure. Assess the QTc interval via an ECG at baseline, and during treatment as clinically indicated. Obtain serum electrolytes (including potassium, calcium, phosphorus, and magnesium) at baseline and during treatment as clinically indicated, and correct electrolyte abnormalities.. 5.3 Tachycardia and Hypotension. Tachycardia and hypotension (including orthostatic hypotension) have been reported in patients treated with haloperidol [see Adverse Reactions (6.1)] Orthostatic vital signs should be monitored in patients who are at risk for hypotension (e.g., geriatric patients, patients with dehydration, hypovolemia, and concomitantly treated with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. Should hypotension occur and vasopressor be required, epinephrine must not be used since HALDOL DECANOATE may block its vasopressor activity, and paradoxically lower blood pressure. Instead, metaraminol, phenylephrine or norepinephrine should be used.. 5.4 Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis. In placebo-controlled trials, elderly patients with dementia-related psychosis treated with antipsychotics had an increased risk of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) including fatalities, compared to those treated with placebo. The mechanism for this increased risk is not known.HALDOL DECANOATE is not approved for the treatment of patients with dementia-related psychosis. HALDOL DECANOATE should be used with caution in patients with schizophrenia who have risk factors for cerebrovascular adverse reactions.. 5.5 Tardive Dyskinesia. Tardive dyskinesia (TD) may develop in patients treated with antipsychotic drugs, including HALDOL DECANOATE [see Adverse Reactions (6.1)] TD can develop after relatively brief treatment period at low dosages and may also occur after discontinuation of treatment. If antipsychotic treatment is discontinued, TD may partially or completely remit. Antipsychotic treatment, however, may suppress or partially suppress the signs and symptoms of TD and may mask the underlying process. The effect that symptomatic suppression has upon the long-term course of TD is unknown. The TD risk in patients treated with antipsychotic drugs appears to be highest among the elderly, especially elderly women, but it is not possible to predict, which patients are likely to develop TD. The TD risk and the likelihood that TD will become irreversible increase with the duration of antipsychotic drug treatment and the cumulative dosage.In patients who require chronic antipsychotic treatment, use the lowest dosage and the shortest duration of treatment that produces satisfactory clinical response. Periodically reassess the need for continued treatment. If signs and symptoms of TD appear in HALDOL DECANOATE-treated patients, consider drug discontinuation. However, some patients may require HALDOL DECANOATE treatment despite the presence of TD.. 5.6 Neuroleptic Malignant Syndrome. Neuroleptic Malignant Syndrome (NMS), potentially fatal symptom complex, has been reported in association with the use of antipsychotic drugs [see Adverse Reactions (6.1)] Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability, and additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue HALDOL DECANOATE and provide intensive symptomatic treatment and monitoring.. 5.7 Neurological Adverse Reactions in Patients with Parkinsons Disease or Dementia with Lewy Bodies. Patients with Parkinsons disease or Dementia with Lewy bodies may experience increased sensitivity to haloperidol. Manifestations of this increased sensitivity include severe extrapyramidal symptoms (e.g., tremor, rigidity, bradykinesia), confusion, sedation, and falls. HALDOL DECANOATE is contraindicated in patients with Dementia with Lewy bodies and in patients with Parkinsons disease.. 5.8 Seizures. HALDOL DECANOATE may lower the seizure threshold. HALDOL DECANOATE is generally not recommended in patients receiving antiseizure drugs or have history of seizures or EEG abnormalities. If clinically indicated, maintain patients taking HALDOL DECANOATE on adequate antiseizure therapy.. 5.9 Hypersensitivity Reactions. There have been postmarketing reports of hypersensitivity reactions with haloperidol including anaphylactic reaction, angioedema, dermatitis exfoliative, hypersensitivity vasculitis, rash, urticaria, face edema, laryngeal edema, bronchospasm, and laryngospasm [see Adverse Reactions (6.2)] HALDOL DECANOATE is contraindicated in patients with known hypersensitivity to haloperidol or any components of HALDOL DECANOATE.. 5.10 Falls. Antipsychotics, including HALDOL DECANOATE, may cause somnolence, orthostatic hypotension, motor instability and sensory abnormality, which may lead to falls and, consequently, fractures and other injuries.If patients have condition (or take concomitant drugs) that could exacerbate these effects, complete fall risk assessments when initiating HALDOL DECANOATE treatment and periodically during long-term treatment.. 5.11 Potential for Cognitive and Motor Impairment. HALDOL DECANOATE may impair judgement, thinking, or motor skills. Inform patients of the risk and advise them to not drive motor vehicle or operate hazardous machinery until they are reasonably certain that treatment with HALDOL DECANOATE does not impair their cognitive and motor functions.. 5.12 Risk of Encephalopathic Syndrome with Concomitant Use of Lithium. An encephalopathic syndrome, characterized by weakness, lethargy, fever, tremulousness, confusion, extrapyramidal symptoms, leukocytosis, and elevated serum enzymes (AST, ALT, GGT, alkaline phosphatase, CK, and LDH), BUN, and fasting blood sugar, followed by irreversible brain damage has occurred in few patients treated with concomitant haloperidol and lithium.Monitor patients who concomitantly use HALDOL DECANOATE and lithium closely for early signs of neurological toxicity, and discontinue HALDOL DECANOATE or both HALDOL DECANOATE and lithium promptly if such signs appear.. 5.13 Leukopenia, Neutropenia, and Agranulocytosis. Leukopenia, neutropenia and agranulocytosis (including fatal cases) have been reported during treatment with antipsychotic drugs, including HALDOL DECANOATE [see Adverse Reactions (6.2)] Possible risk factors for antipsychotic drug-associated leukopenia and neutropenia include pre-existing low WBC and history of drug-induced leukopenia and neutropenia.Perform frequent complete blood count (CBC) monitoring during the first few months of HALDOL DECANOATE therapy in patients with history of clinically significant low WBC, drug-induced leukopenia or neutropenia. Consider discontinuing HALDOL DECANOATE in patients who have clinically significant decline in their WBC in the absence of other causative factors. Discontinue HALDOL DECANOATE in patients with clinically significant neutropenia or an absolute neutrophil count of <1,000/mm 3and monitor closely until the neutropenia resolves. 5.14 Hyperprolactinemia. Antipsychotic drugs elevate prolactin levels during acute and chronic use and may result in galactorrhea, amenorrhea, gynecomastia, and impotence which have been reported with antipsychotic drugs [see Adverse Reactions (6.1, 6.2)and Use in Specific Populations (8.3)] Published epidemiologic studies have shown inconsistent results regarding the potential association between hyperprolactinemia and breast cancer [see Nonclinical Toxicology (13.1)] . 5.15 Risk of Severe Neurotoxicity in Patients with Thyrotoxicosis. Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic drugs, including HALDOL DECANOATE.