arly hypokalemia and hypomagnesemia], drugs known to prolong qtc, underlying cardiac abnormalities, hypothyroidism, and familial long qt-syndrome). haloperidol injection is not approved for intravenous administration. if haloperidol is administered intravenously, the ecg should be monitored for qtc prolongation and arrhythmias. 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 haloperidol, other antipsychotics, or other patient populations. haloperidol should be used with caution in patients with risk factors for cerebrovascular adverse reactions. tardive dyskinesia a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs (see adverse reactions ). 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 a manner that is most likely to minimize the occurrence of tardive dyskinesia. chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. in patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. the need for continued treatment should be reassessed periodically. if signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. however, some patients may require treatment despite the presence of the syndrome. neuroleptic malignant syndrome (nms) a potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome (nms) has been reported in association with antipsychotic drugs (see adverse reactions ). 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 a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms. other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (cns) pathology. the management of nms should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. there is no general agreement about specific pharmacological treatment regimens for uncomplicated nms. if a patient requires antipsychotic drug treatment after recovery from nms, the potential reintroduction of drug therapy should be carefully considered. the patient should be carefully monitored, since recurrences of nms have been reported. hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with haloperidol. neurological adverse reactions in patients with parkinson’s disease or dementia with lewy bodies patients with parkinson’s disease or dementia with lewy bodies are reported to have an increased sensitivity to antipsychotic medication. manifestations of this increased sensitivity with haloperidol treatment include severe extrapyramidal symptoms, confusion, sedation, and falls. in addition, haloperidol may impair the antiparkinson effects of levodopa and other dopamine agonists. haloperidol is contraindicated in patients with parkinson’s 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 ). haloperidol 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 haloperidol, 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 for patients receiving repeated doses. usage in pregnancy rats or rabbits administered oral haloperidol at doses of 0.5 to 7.5 mg/kg. which are approximately 0.2 to 7 times the maximum recommended human dose (mrhd) of 20 mg/day based on mg/m2 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 a dose of 0.5 mg/kg, which is approximately 0.1 times the mrhd based on mg/m 2 body surface area. there are no well controlled studies with haloperidol in pregnant women. there are reports, however, of cases of limb malformations observed following maternal use of haloperidol along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. causal relationships were not established in these cases. since such experience does not exclude the possibility of fetal damage due to haloperidol, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. infants should not be nursed during drug treatment. non-teratogenic effects neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. there have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. these complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. haloperidol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. combined use of haloperidol and lithium an encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, bun, and fasting blood sugar) followed by irreversible brain damage has occurred in a few patients treated with lithium plus haloperidol. a causal relationship between these events and the concomitant administration of lithium and haloperidol has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. general a number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including haloperidol. it has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. although not reported with haloperidol, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs.

ted schizophrenic patient with moderately severe to very severe symptoms. depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory. the maximum dose is 20 mg/day. controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. switchover procedure an oral form should supplant the injectable as soon as practicable. in the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. for an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover. in this way, dosage adjustments, either upward or downward, can be quickly accomplished. depending on the patient’s clinical status, the first oral dose should be given within 12 to 24 hours following the last parenteral dose.

ol in the following: • 284 patients who participated in 3 double-blind, placebo-controlled clinical trials with haloperidol (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. based on the pooled safety data, the most common adverse reactions in haloperidol-treated patients from these double-blind placebo-controlled clinical trials (≥5%) were: extrapyramidal disorder, hyperkinesia, tremor, hypertonia, dystonia, and somnolence. adverse reactions reported at ≥1% incidence in double-blind placebo-controlled clinical trials with oral haloperidol adverse reactions occurring in ≥1% of haloperidol-treated patients and at higher rate than placebo in 3 double-blind, parallel, placebo-controlled, clinical trials with the oral formulation are shown in table 1. table 1: adverse reactions occurring in ≥1% of haloperidol-treated patients in a double-blind, parallel placebo-controlled clinical trials (oral haloperidol) system/organ class adverse reaction haloperidol (n=284) % placebo (n=282) % gastrointestinal disorders constipation dry mouth salivary hypersecretion 4.2 1.8 1.2 1.8 0.4 0.7 nervous system disorders extrapyramidal disorder a hyperkinesia tremor hypertonia dystonia bradykinesia somnolence 50.7 10.2 8.1 7.4 6.7 4.2 5.3 16.0 2.5 3.6 0.7 0.4 0.4 1.1 a represents the total reporting rate for extrapyramidal disorder (reported term) and individual symptoms of extrapyramidal disorder, including events that did not meet the threshold of ≥1% for inclusion in this table additional adverse reactions reported in double-blind, placebo-or active comparator-controlled clinical trials with injectable or oral haloperidol additional adverse reactions that are listed below were reported by haloperidol-treated patients in double-blind, active comparator-controlled clinical trials with the injectable or oral formulation, or at <1% incidence in double-blind, parallel, placebo-controlled, clinical trials with the oral formulation. cardiac disorders: tachycardia endocrine disorders: hyperprolactinemia eye disorders: vision blurred investigations: weight increased musculoskeletal and connective tissue disorders: torticollis, trismus, muscle rigidity, muscle twitching nervous system disorders: akathisia, dizziness, dyskinesia, hypokinesia, neuroleptic malignant syndrome, nystagmus, oculogyric crisis, parkinsonism, sedation, tardive dyskinesia psychiatric disorders: loss of libido, restlessness reproductive system and breast disorders: amenorrhea, galactorrhea, dysmenorrhea, erectile dysfunction, menorrhagia, breast discomfort skin and subcutaneous tissue disorders: acneiform skin reactions vascular disorders: hypotension, orthostatic hypotension adverse reactions identified in clinical trials with haloperidol decanoate the adverse reactions listed below were identified in clinical trials with haloperidol decanoate (long-acting depot formulation), and reflect exposure to the active moiety 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. nervous system disorders: akinesia, cogwheel rigidity, masked facies. 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 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, headache, 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 to report suspected adverse reactions, contact gland pharma at 864-879-9994 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

rease 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 2 body surface area. in female mice there was a 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 2 body surface area and there was a 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 , a factor of potential importance if the prescription of these drugs is contemplated in a patient with a 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. neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. there are no well controlled studies with haloperidol in pregnant women. there are reports, however, of cases of limb malformations observed following maternal use of haloperidol along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. causal relationships were not established in these cases. since such experience does not exclude the possibility of fetal damage due to haloperidol, this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus.