Side Effects of Haldol (haloperidol)

Haldol (haloperidol) is an antipsychotic medication used to treat schizophrenia and acute psychosis, and to control tics and vocal utterances that are part of Tourette's syndrome. 

Haldol interferes with the effects of neurotransmitters in the brain which are the chemical messengers that nerves manufacture and release to communicate with one another. 

Haldol blocks receptors for the neurotransmitters (specifically the dopamine and serotonin type 2 receptors) on the nerves. As a result, the nerves are not "activated" by the neurotransmitters released by other nerves.

Common side effects of Haldol include

• extrapyramidal effects (sudden, often jerky, involuntary motions of the head, neck, arms, body, or eyes, muscle stiffness, akathisia, Parkinsonism),
• dizziness,
• hyperactivity,
• tiredness, and
• nausea.

Other important side effects of Haldol include

• sedation,
• weight gain,
• erectile dysfunction,
• menstrual irregularities,
• insomnia,
• breast tissue enlargement in males (gynecomastia),
• dry mouth,
• vomiting,
• constipation, and
• dizziness on standing (orthostatic hypotension).

Serious side effects of Haldol include

• abnormal heart beats,
• sudden death, seizures,
• decreases in red and white blood cells, and
• withdrawal symptoms.

Elderly patients with dementia-related psychosis and treated with antipsychotic drugs such as Haldol are at an increased risk of death.

Drug interactions of Haldol include alcohol and other drugs that can cause sedation such as

• benzodiazepines (such as diazepam, lorazepam, clonazepam, and alprazolam),
• narcotics (such as oxycodone, hydrocodone, dilaudid, codeine, and propoxyphene),
• tricyclic antidepressants (such as amitriptyline, imipramine, and desipramine),
• antihistamines (such as hydroxyzine, diphenhydramine, and clemastine),
• antihypertensive medications (such as clonidine and propranolol) because Haldol causes sedation, and sedation may be greater if Haldol is taken with these drugs. 

Carbamazepine may increase the elimination of Haldol, rendering the Haldol less effective. 

Rifampin may decrease the elimination of Haldol, increasing the risk of side effects from Haldol. 

Neonates exposed to antipsychotics such as Haldol during the 3rd trimester of pregnancy may develop withdrawal symptoms and extrapyramidal symptoms. Haldol is secreted into breast milk. It should not be used while breastfeeding.

The most common side effects associated with Haldol are:

• extrapyramidal effects (sudden, often jerky, involuntary motions of the head, neck, arms, body, or eyes, muscle stiffness, akathisia, Parkinsonism),
• dizziness,
• hyperactivity,
• tiredness, and
• nausea.

Other important side effects are:

• sedation,
• weight gain,
• erectile dysfunction,
• menstrual irregularities,
• insomnia,
• gynecomastia,
• dry mouth, 
• vomiting, and
• constipation

Haldol may cause a condition called "orthostatic hypotension" during the early phase of treatment (first week or two). Orthostatic hypotension causes patients to become dizzy upon arising from a lying or sitting position because of a drop in blood pressure.

Haldol also may cause

• abnormal heart beats,
• sudden death,
• seizures,
• decreases in red and white blood cells, and
• withdrawal symptoms.

Elderly patients with dementia-related psychosis and treated with antipsychotic drugs such as Haldol are at an increased risk of death.

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

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

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

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

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 QT-prolongation has been observed during Haldol treatment, caution is advised when prescribing to a patient with QT-prolongation conditions (long QT-syndrome, hypokalemia, electrolyte imbalance) or to patients receiving medications known to prolong the QT-interval or known to cause electrolyte imbalance.
• 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 is discontinued because of the difference in excretion rates.
• If both 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.
• As with other antipsychotic agents, it should be noted that Haldol may be capable of potentiating CNS depressants such as anesthetics, opiates and alcohol.
• Ketoconazole is a potent inhibitor of CYP3A4. Increases in QTc have been observed when haloperidol was given in combination with the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to reduce the haloperidol dosage.

Pharmacokinetic Interactions

The Effect Of Other Drugs On Haloperidol

• Haloperidol is metabolized by several routes, including the glucuronidation and the cytochrome P450 enzyme system. Inhibition of these routes of metabolism by another drug may result in increased haloperidol concentrations and potentially increase the risk of certain adverse events, including QT-prolongation.

Drugs Characterized As Substrates, Inhibitors Or Inducers Of CYP3A4, CYP2D6 Or Glucuronidation

• In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterized as substrates or inhibitors of CYP3A4 or CYP2D6 isoenzymes, such as itraconazole, nefazodone, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine.
• 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.
• When prolonged treatment (1-2 weeks) with enzyme-inducing drugs such as rifampin or carbamazepine is added to Haldol therapy, this results in a significant reduction of haloperidol plasma levels.

Rifampin

• In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline.
• In 5 other schizophrenic patients treated with haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3- fold increase in haloperidol concentrations.

Carbamazepine

• In a study in 11 schizophrenic patients co-administered haloperidol and increasing doses of carbamazepine, haloperidol plasma concentrations decreased linearly with increasing carbamazepine concentrations.
• Thus, careful monitoring of clinical status is warranted when enzyme inducing drugs such as rifampin or carbamazepine are administered or discontinued in haloperidol-treated patients. During combination treatment, the Haldol dose should be adjusted, when necessary.
• After discontinuation of such drugs, it may be necessary to reduce the dosage of Haldol.

Valproate

• Sodium valproate, a drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.