Haloperidol (Page 3 of 5)

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, and 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/m² 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/m² 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
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.