Haloperidol can be administered orally, intravenously, subcutaneously, or intramuscularly. Parenteral doses are roughly twice as potent as oral doses. Peak plasma concentrations are achieved 2 to 4 hours after an oral dose, and measurable plasma concentrations occur 15 to 30 minutes after intramuscular administration. Haloperidol may cause fewer EPS when administered intravenously. The EPS can be treated with agents such as benztropine in doses of 1 to 2 mg once or twice a day. Neuroleptic malignant syndrome, a rare complication with haloperidol use, is characterized by hyperthermia, increased mental confusion, leukocytosis, muscular rigidity, myoglobinuria, and high serum creatinine phosphokinase. Injectable haloperidol is approved by the FDA only for intramuscular administration. However, it is frequently administered intravenously to treat agitated delirium.
Intravenous administration and higher doses of haloperidol have been associated with risk of sudden death due to Torsades de Pointes (TdP) and QTc prolongation. In this context, an FDA alert raised concerns about intravenous use of haloperidol. The updated labeling of haloperidol includes a strong warning about the TdP and QTc prolongation issues, especially in patients with specific cardiovascular risk factors, and recommends consideration of alternative agents. The FDA alert also recommends extreme caution and close electrocardiogram monitoring if haloperidol is administered intravenously. The FDA alert is based on case reports and small case-control studies. There are no randomized studies investigating this issue, and the data from case reports and case-control studies are confounded by multiple factors (e.g., comorbid conditions and other agents known to cause QTc prolongation).
Evidence suggests that QTc prolongation and TdP might be primarily associated with higher haloperidol doses (6 mg or higher). No cases of QTc prolongation or TdP have been reported with a cumulative intravenous dose smaller than 2 mg. The presence of certain risk factors might increase the risk of QTc prolongation and TdP. Major risk factors include the following:
- Pre-existing heart disease.
- Electrolyte imbalance.
- Concomitant pro-arrhythmic agents and other agents affecting cardiac function.
- Mechanical ventilation.
- High baseline QTc (>450 msec).
Elderly patients, female patients, and patients with endocrine disorders (e.g., diabetes) may carry a higher risk of QTc and TdP. In patients with cancer, special attention should be paid to past or concomitant use of cardiotoxic chemotherapy regimens such as anthracycline-based regimens. Baseline and continuous ECG monitoring is recommended in patients receiving high doses of haloperidol and/or with known risk factors for developing QTc prolongation. Many of the alternatives (i.e., currently available typical and atypical antipsychotics) are also associated with QTc prolongation and TdP.
In select cases, the risk-benefit equation might favor intravenous use of haloperidol, especially in patients with established intravenous access; in addition, no other currently available antipsychotics can be delivered intravenously. Before the newer atypical antipsychotics became available, chlorpromazine was considered an alternative to haloperidol, although it is associated with orthostatic hypotension and a greater level of sedation.