HALOPERIDOL LACTATE (Page 3 of 4)
Information for Patients
Haloperidol may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No mutagenic potential of haloperidol 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 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 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to 5 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, although a relatively greater number of rats survived to the end of the study in high-dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of a 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 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.
Nursing Mothers
Since haloperidol is excreted in human breast milk, infants should not be nursed during drug treatment with haloperidol.
Pediatric Use
Safety and effectiveness in pediatric patients 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
The following adverse reactions are discussed in more detail in other sections of the labeling:
- WARNINGS, Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- WARNINGS, Cardiovascular Effects
- WARNINGS, Tardive Dyskinesia
- WARNINGS, Neuroleptic Malignant Syndrome
- WARNINGS, Hypersensitivity Reactions
- WARNINGS, Falls
- WARNINGS, Usage in Pregnancy
- WARNINGS, Combined Use of Haloperidol and Lithium
- WARNINGS, General
- PRECAUTIONS, Leukopenia, Neutropenia, and Agranulocytosis
- PRECAUTIONS, Withdrawal Emergent Dyskinesia
- PRECAUTIONS, Other
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.
The data described below reflect exposure to haloperidol in 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 Double-Blind, Parallel Placebo-Controlled Clinical Trials (Oral Haloperidol)
System/Organ Class Adverse Reaction | Haloperidol (n=284) % | Placebo (n=282) % |
Gastrointestinal Disorders | ||
Constipation | 4.2 | 1.8 |
Dry mouth | 1.8 | 0.4 |
Salivary hypersecretion | 1.2 | 0.7 |
Nervous System Disorders | ||
Extrapyramidal disorder a | 50.7 | 16.0 |
Hyperkinesia | 10.2 | 2.5 |
Tremor | 8.1 | 3.6 |
Hypertonia | 7.4 | 0.7 |
Dystonia | 6.7 | 0.4 |
Bradykinesia | 4.2 | 0.4 |
Somnolence | 5.3 | 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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