HALOPERIDOL DECANOATE (Page 3 of 5)

Carcinogenesis, Mutagenesis, 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 e ffects 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 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 di fferences 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.

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/m2 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 haloperidol 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 haloperidol, haloperidol decanoate should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus.

Non-Teratogenic Eff ects

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 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

The following adverse reactions are discussed in more detail in other sections of the labeling:

• WARNINGS, Increased mortality in Elderly Patients with Dementia-Related Psychosis
• WARNINGS, Cardiovascular Effects
• WARNINGS, Tardive Dyskinesia
• WARNINGS, Neuroleptic Malignant Syndrome
• WARNINGS, Hypersensitivity Reactions
• WARNINGS, Falls
• WARNINGS, Combined Use of Haloperidol and Lithium
• WARNINGS, General
• PRECAUTIONS, Leukopenia, Neutropenia, and Agranulocytosis
• PRECAUTIONS, Other
• PRECAUTIONS, Usage in Pregnancy

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.

The data described below reflect exposure to haloperidol in 410 patients who participated in 13 clinical trials with haloperidol decanoate (15 to 500 mg/month) in the treatment of schizophrenia or schizoaffective disorder. These clinical trials comprised:

• 1 double-blind, active comparator-controlled trial with fluphenazine decanoate.
• 2 trials comparing the decanoate formulation to oral haloperidol.
• 9 open-label trials.
• 1 dose-response trial.

The most common adverse reactions in haloperidol decanoate-treated patients in the double-blind, active comparator-controlled clinical trial with fluphenazine decanoate (≥5%) were: Parkinsonism, and oculogyric crisis.

Adverse Reactions Reported at ≥1% Incidence in a Double-Blind Active Comparator-Controlled Clinical Trial

Adverse reactions occurring in 1% of haloperidol decanoate-treated patients in a double-blind, clinical trial with the active comparator fluphenazine decanoate are shown in Table 1.

Table 1 . Adverse Reactions Reported by ≥1% of Haloperidol Decanoate-treated Patients in a Double- Blind Active Comparator-Controlled Clinical Trial with Fluphenazine Decanoate

a 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
System/Organ Class Adverse Reaction	Haloperidol decanoate (n=36) %	Fluphenazine decanoate (n=36) %
Gastrointestinal Disorders
Abdominal pain	2.8	0
Nervous System Disorders
Extrapyramidal disordera:
Parkinsonism	30.6	44.4
Oculogyric crisis	5.6	0
Akinesia	2.8	22.2
Akathisia	2.8	13.9
Tremor	2.8	0
Headache	2.8	0

Additional Adverse Reactions Reported in Double-Blind, Comparator, Open-Label and Dose-Response Clinical Trials

Additional adverse reactions that are listed below were reported by haloperidol decanoate-treated patients in comparator, open-label, and dose-response clinical trials, or at <1% incidence in a double-blind, active comparator-controlled clinical trial with fluphenazine decanoate.

Cardiac Disorders: Tachycardia

Endocrine Disorders: Hyperprolactinemia

Eye Disorders: Vision blurred

Gastrointestinal Disorders: Constipation, Dry mouth, Salivary hypersecretion

General Disorders and Administration Site Conditions: Injection site reaction

Investigations: Weight increased

Musculoskeletal and Connective Tissue Disorders: Muscle rigidity

Nervous System Disorders: Dyskinesia, Dystonia, Cogwheel rigidity, Hypertonia, Masked Facies, Sedation, Somnolence

Reproductive System and Breast Disorders: Erectile dysfunction

Adverse Reactions Identified in Clinical Trials with Haloperidol (Non-Decanoate Formulations)

The adverse reactions listed below were identified with non-decanoate formulations, and reflect exposure to the active moiety haloperidol in the following:

• 284 patients who participated in 3 double-blind, placebo-controlled clinical trials with haloperidol (injection or oral formulation, 2 to 20 mg/day); two trials were in the treatment of schizophrenia and one in the treatment of bipolar disorder.
• 1295 patients who participated in 16 double-blind, active comparator-controlled clinical trials with haloperidol (injection or oral formulation, 1 to 45 mg/day) in the treatment of schizophrenia.

Musculoskeletal and Connective Tissue Disorders: Torticollis, Trismus, Muscle twitching

Nervous System Disorders: Neuroleptic malignant syndrome, Tardive dyskinesia, Bradykinesia, Hyperkinesia, Hypokinesia, Dizziness, Nystagmus

Psychiatric Disorders: Loss of libido, Restlessness

Reproductive System and Breast Disorders: Amenorrhea, Galactorrhea, Dysmenorrhea, Menorrhagia, Breast discomfort

Skin and Subcutaneous Tissue Disorders: Acneiform skin reactions

Vascular Disorders: Hypotension, Orthostatic hypotension