Interactions between Haloperidol and Nateglinide

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.

The use of most miscellaneous antipsychotics is contraindicated in patients with severe central nervous system depression or comatose states from any cause (e.g., lesion, disease, drug or alcohol induced).

The use of neuroleptic agents is contraindicated in patients with acute alcohol intoxication exhibiting depressed vital signs. The central nervous system depressant effects of neuroleptic agents may be additive with those of alcohol. Severe respiratory depression and respiratory arrest may occur. Therapy with neuroleptic agents should be administered cautiously in patients who might be prone to acute alcohol intake.

Antipsychotics can lower the seizure threshold and trigger seizures in a dose-dependent manner. Seizures have been reported in patients receiving antipsychotic therapy and may occur in epileptic patients even with maintenance of routine anticonvulsant treatment. Therapy with antipsychotics should be administered cautiously in patients with a history of seizures or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism. High dosages should be avoided if possible.

The use of neuroleptic agents is contraindicated in comatose patients and patients with severe central nervous system depression. Neuroleptic agents may potentiate the CNS and respiratory depression in these patients.

The use of most miscellaneous antipsychotics is contraindicated in patients with severe central nervous system depression or comatose states from any cause (e.g., lesion, disease, drug or alcohol induced).

The use of oral hypoglycemic agents may be associated with an increased risk of cardiovascular mortality compared to treatment with diet alone or diet with insulin. This warning is based on the University Group Diabetes Program (UGDP) study, a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. Patients treated with diet plus a fixed dosage of either tolbutamide (a sulfonylurea) or phenformin (a biguanide) for 5 to 8 years had a cardiovascular mortality rate approximately 2.5 times that of patients treated with diet alone, resulting in discontinuation of both these treatments in the study. Despite controversy regarding interpretation of these results, clinicians and patients should be aware of the potential risk when making treatment decisions for diabetes, particularly in the presence of underlying cardiovascular disease. Data are not available for other sulfonylureas or biguanides, nor for hypoglycemic agents belonging to other classes. However, given the similarities in chemical structure and/or mode of action, the same caution should be applied.

Neuroleptic agents may cause hypotension (including orthostatic hypotension), reflex tachycardia, increased pulse rate, syncope and dizziness, particularly during initiation of therapy or rapid escalation of dosage. Tolerance to the hypotensive effects often develops after a few doses to a few weeks. Rarely, fatal cardiac arrest has occurred secondary to severe hypotension. Other reported adverse cardiovascular effects include hypertension, edema, arrhythmias, thrombophlebitis, myocarditis, angina, myocardial infarction, congestive heart failure, and ECG abnormalities such as PR and QT interval prolongation, diffuse T-wave flattening, and ST segment depression. Therapy with neuroleptic agents should be administered cautiously in patients with severe cardiovascular disease, pheochromocytoma, a predisposition to hypotension, or conditions that could be exacerbated by hypotension such as a history of myocardial infarction, angina, or ischemic stroke. Close monitoring of cardiovascular status, including ECG changes, is recommended at all dosages. If parenteral therapy is given, patients should be in a supine position during administration and for at least 30 to 60 minutes afterwards. Patients who experience orthostatic hypotension should be cautioned not to rise too abruptly. Occasionally, when severe, hypotension may require treatment with vasoconstrictive agents such as norepinephrine or phenylephrine. Epinephrine should not be used, however, since neuroleptic agents can reverse its vasopressor effects and cause a further lowering of blood pressure.

Antipsychotics can lower the seizure threshold and trigger seizures in a dose-dependent manner. Seizures have been reported in patients receiving antipsychotic therapy and may occur in epileptic patients even with maintenance of routine anticonvulsant treatment. Therapy with antipsychotics should be administered cautiously in patients with a history of seizures or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism. High dosages should be avoided if possible.

Elderly patients with dementia- related psychosis treated with antipsychotic drugs are at increased risk of death. Most of these drugs are not approved for the treatment of patients with dementia- related psychosis.

Antipsychotic drugs are not approved for the treatment of patients with dementia-related psychosis. Older patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death; although the causes were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. A causal relationship with antipsychotic use has not been established. In controlled trials in older patients with dementia-related psychosis, patients randomized to risperidone, aripiprazole, and olanzapine had higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, compared to patients treated with placebo.

The use of meglitinides is contraindicated in patients with type I diabetes or for the treatment of diabetic ketoacidosis, with or without coma.

The use of meglitinides is contraindicated in patients with type I diabetes or for the treatment of diabetic ketoacidosis, with or without coma.

Neuroleptic agents may cause hypotension (including orthostatic hypotension), reflex tachycardia, increased pulse rate, syncope and dizziness, particularly during initiation of therapy or rapid escalation of dosage. Tolerance to the hypotensive effects often develops after a few doses to a few weeks. Rarely, fatal cardiac arrest has occurred secondary to severe hypotension. Other reported adverse cardiovascular effects include hypertension, edema, arrhythmias, thrombophlebitis, myocarditis, angina, myocardial infarction, congestive heart failure, and ECG abnormalities such as PR and QT interval prolongation, diffuse T-wave flattening, and ST segment depression. Therapy with neuroleptic agents should be administered cautiously in patients with severe cardiovascular disease, pheochromocytoma, a predisposition to hypotension, or conditions that could be exacerbated by hypotension such as a history of myocardial infarction, angina, or ischemic stroke. Close monitoring of cardiovascular status, including ECG changes, is recommended at all dosages. If parenteral therapy is given, patients should be in a supine position during administration and for at least 30 to 60 minutes afterwards. Patients who experience orthostatic hypotension should be cautioned not to rise too abruptly. Occasionally, when severe, hypotension may require treatment with vasoconstrictive agents such as norepinephrine or phenylephrine. Epinephrine should not be used, however, since neuroleptic agents can reverse its vasopressor effects and cause a further lowering of blood pressure.

Neuroleptic agents may cause hypotension (including orthostatic hypotension), reflex tachycardia, increased pulse rate, syncope and dizziness, particularly during initiation of therapy or rapid escalation of dosage. Tolerance to the hypotensive effects often develops after a few doses to a few weeks. Rarely, fatal cardiac arrest has occurred secondary to severe hypotension. Other reported adverse cardiovascular effects include hypertension, edema, arrhythmias, thrombophlebitis, myocarditis, angina, myocardial infarction, congestive heart failure, and ECG abnormalities such as PR and QT interval prolongation, diffuse T-wave flattening, and ST segment depression. Therapy with neuroleptic agents should be administered cautiously in patients with severe cardiovascular disease, pheochromocytoma, a predisposition to hypotension, or conditions that could be exacerbated by hypotension such as a history of myocardial infarction, angina, or ischemic stroke. Close monitoring of cardiovascular status, including ECG changes, is recommended at all dosages. If parenteral therapy is given, patients should be in a supine position during administration and for at least 30 to 60 minutes afterwards. Patients who experience orthostatic hypotension should be cautioned not to rise too abruptly. Occasionally, when severe, hypotension may require treatment with vasoconstrictive agents such as norepinephrine or phenylephrine. Epinephrine should not be used, however, since neuroleptic agents can reverse its vasopressor effects and cause a further lowering of blood pressure.

Neuroleptic agents may cause hypotension (including orthostatic hypotension), reflex tachycardia, increased pulse rate, syncope and dizziness, particularly during initiation of therapy or rapid escalation of dosage. Tolerance to the hypotensive effects often develops after a few doses to a few weeks. Rarely, fatal cardiac arrest has occurred secondary to severe hypotension. Other reported adverse cardiovascular effects include hypertension, edema, arrhythmias, thrombophlebitis, myocarditis, angina, myocardial infarction, congestive heart failure, and ECG abnormalities such as PR and QT interval prolongation, diffuse T-wave flattening, and ST segment depression. Therapy with neuroleptic agents should be administered cautiously in patients with severe cardiovascular disease, pheochromocytoma, a predisposition to hypotension, or conditions that could be exacerbated by hypotension such as a history of myocardial infarction, angina, or ischemic stroke. Close monitoring of cardiovascular status, including ECG changes, is recommended at all dosages. If parenteral therapy is given, patients should be in a supine position during administration and for at least 30 to 60 minutes afterwards. Patients who experience orthostatic hypotension should be cautioned not to rise too abruptly. Occasionally, when severe, hypotension may require treatment with vasoconstrictive agents such as norepinephrine or phenylephrine. Epinephrine should not be used, however, since neuroleptic agents can reverse its vasopressor effects and cause a further lowering of blood pressure.

The use of neuroleptic agents in the presence of thyrotoxicosis has been associated with severe neurotoxicity that includes rigidity and inability to walk or talk. Therapy with haloperidol should be administered cautiously in patients with thyrotoxicosis or hyperthyroidism.

Neuroleptic agents may cause hypotension (including orthostatic hypotension), reflex tachycardia, increased pulse rate, syncope and dizziness, particularly during initiation of therapy or rapid escalation of dosage. Tolerance to the hypotensive effects often develops after a few doses to a few weeks. Rarely, fatal cardiac arrest has occurred secondary to severe hypotension. Other reported adverse cardiovascular effects include hypertension, edema, arrhythmias, thrombophlebitis, myocarditis, angina, myocardial infarction, congestive heart failure, and ECG abnormalities such as PR and QT interval prolongation, diffuse T-wave flattening, and ST segment depression. Therapy with neuroleptic agents should be administered cautiously in patients with severe cardiovascular disease, pheochromocytoma, a predisposition to hypotension, or conditions that could be exacerbated by hypotension such as a history of myocardial infarction, angina, or ischemic stroke. Close monitoring of cardiovascular status, including ECG changes, is recommended at all dosages. If parenteral therapy is given, patients should be in a supine position during administration and for at least 30 to 60 minutes afterwards. Patients who experience orthostatic hypotension should be cautioned not to rise too abruptly. Occasionally, when severe, hypotension may require treatment with vasoconstrictive agents such as norepinephrine or phenylephrine. Epinephrine should not be used, however, since neuroleptic agents can reverse its vasopressor effects and cause a further lowering of blood pressure.

The central dopaminergic blocking effects of neuroleptic agents may precipitate or aggravate a potentially fatal symptom complex known as neuroleptic malignant syndrome (NMS). NMS is observed most frequently when high-potency agents like haloperidol are administered intramuscularly, but may occur with any neuroleptic agent given for any length of time. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria, and acute renal failure. Neuroleptic agents should not be given to patients with active NMS and should be immediately discontinued if currently being administered in such patients. In patients with a history of NMS, introduction or reintroduction of neuroleptic agents should be carefully considered, since NMS may recur.

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with the use of antipsychotic drugs. The diagnostic evaluation is complicated and the management requires immediate discontinuation of the antipsychotic therapy and intensive symptomatic treatment and medical monitoring. If a patient that has recovered from NMS requires antipsychotic drug treatment again, the reintroduction of therapy should be carefully considered as NMS recurrences have been reported.

The use of neuroleptic agents is associated with pseudo- parkinsonian symptoms such as akinesia, bradykinesia, tremors, pill- rolling motion, cogwheel rigidity, and postural abnormalities including stooped posture and shuffling gait. The onset is usually 1 to 2 weeks following initiation of therapy or an increase in dosage. Older neuroleptic agents such as haloperidol are more likely to induce these effects. The manufacturers of haloperidol consider its use to be contraindicated in patients with Parkinson's disease.

The use of neuroleptic agents is contraindicated in comatose patients and patients with severe central nervous system depression. Neuroleptic agents may potentiate the CNS and respiratory depression in these patients.

Hypoglycemia may commonly occur during treatment with insulin and/or oral hypoglycemic agents. Care should be taken in patients who may be particularly susceptible to the development of hypoglycemic episodes during the use of these drugs, including those who are debilitated or malnourished, those with defective counterregulatory mechanisms (e.g., autonomic neuropathy and adrenal or pituitary insufficiency), and those receiving beta-adrenergic blocking agents.

The use of alcohol with haloperidol should be avoided due to possible additive effects and hypotension.

Antipsychotic and neuroleptic drugs can lower the seizure threshold and trigger seizures in a dose-dependent manner. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Therapy with these drugs should be administered cautiously in patients with a history of seizures or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism.

Haloperidol should be administered cautiously to patients with severe cardiovascular disorders because of the possibility of transient hypotension and/or precipitation of anginal pain. In the presence of severe hypotension requiring vasopressor therapy, the preferred drugs may be norepinephrine, phenylephrine, or metaraminol, as usual doses of epinephrine may be ineffective since haloperidol inhibits its vasopressor effect.

Hypoglycemia may commonly occur during treatment with insulin and/or oral hypoglycemic agents. Care should be taken in patients who may be particularly susceptible to the development of hypoglycemic episodes during the use of these drugs, including those who are debilitated or malnourished, those with defective counterregulatory mechanisms (e.g., autonomic neuropathy and adrenal or pituitary insufficiency), and those receiving beta-adrenergic blocking agents.

Hypoglycemia may commonly occur during treatment with insulin and/or oral hypoglycemic agents. Care should be taken in patients who may be particularly susceptible to the development of hypoglycemic episodes during the use of these drugs, including those who are debilitated or malnourished, those with defective counterregulatory mechanisms (e.g., autonomic neuropathy and adrenal or pituitary insufficiency), and those receiving beta-adrenergic blocking agents.

Antipsychotic drugs can elevate serum prolactin concentrations, and this elevation persists during chronic administration. This should be considered if therapy will be prescribed in patients with previously detected breast cancer as one-third of human breast cancers are prolactin-dependent in vitro. Associated disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported. Appropriate laboratory testing and follow-up is advised.

The chronic use of neuroleptic agents can cause persistent elevations in prolactin levels due to antagonism of dopamine D2 receptors. Based on in vitro data, approximately one-third of human breast cancers are thought to be prolactin-dependent. The clinical significance of this observation with respect to long-term neuroleptic therapy is unknown. Chronic administration of neuroleptic drugs has been associated with mammary tumorigenesis in rodent studies but not in human clinical or epidemiologic studies. Until further data are available, therapy with neuroleptic agents should be administered cautiously in patients with a previously detected breast cancer. Caution is also advised in patients with preexisting hyperprolactinemia. Hyperprolactinemia may suppress hypothalamic gonadotrophin releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds; however, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.

Haloperidol should be administered cautiously to patients with severe cardiovascular disorders because of the possibility of transient hypotension and/or precipitation of anginal pain. In the presence of severe hypotension requiring vasopressor therapy, the preferred drugs may be norepinephrine, phenylephrine, or metaraminol, as usual doses of epinephrine may be ineffective since haloperidol inhibits its vasopressor effect.

Neuroleptic agents may cause hypotension (including orthostatic hypotension) and associated reflex tachycardia, syncope or dizziness, particularly during initiation of therapy or rapid escalation of dosage. Tolerance to the hypotensive effects often develops after a few doses to a few months. Rarely, fatal cardiac arrest has occurred secondary to severe hypotension. Therapy with neuroleptic agents should be administered cautiously in patients with conditions that would predispose them to hypotension, such as hypovolemia or dehydration (e.g., due to severe diarrhea or vomiting). In addition, neuroleptic agents can interfere with the body's ability to regulate core body temperature, occasionally producing hyperthermia during strenuous exercise, exposure to hot weather, and concomitant treatment with anticholinergic medications. Patients who are dehydrated may be particularly susceptible.

Neuroleptic agents may cause hypotension (including orthostatic hypotension) and associated reflex tachycardia, syncope or dizziness, particularly during initiation of therapy or rapid escalation of dosage. Tolerance to the hypotensive effects often develops after a few doses to a few months. Rarely, fatal cardiac arrest has occurred secondary to severe hypotension. Therapy with neuroleptic agents should be administered cautiously in patients with conditions that would predispose them to hypotension, such as hypovolemia or dehydration (e.g., due to severe diarrhea or vomiting). In addition, neuroleptic agents can interfere with the body's ability to regulate core body temperature, occasionally producing hyperthermia during strenuous exercise, exposure to hot weather, and concomitant treatment with anticholinergic medications. Patients who are dehydrated may be particularly susceptible.

Antipsychotic and neuroleptic drugs can lower the seizure threshold and trigger seizures in a dose-dependent manner. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Therapy with these drugs should be administered cautiously in patients with a history of seizures or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism.

Antipsychotic drugs can elevate serum prolactin concentrations, and this elevation persists during chronic administration. This should be considered if therapy will be prescribed in patients with previously detected breast cancer as one-third of human breast cancers are prolactin-dependent in vitro. Associated disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported. Appropriate laboratory testing and follow-up is advised.

The chronic use of neuroleptic agents can cause persistent elevations in prolactin levels due to antagonism of dopamine D2 receptors. Based on in vitro data, approximately one-third of human breast cancers are thought to be prolactin-dependent. The clinical significance of this observation with respect to long-term neuroleptic therapy is unknown. Chronic administration of neuroleptic drugs has been associated with mammary tumorigenesis in rodent studies but not in human clinical or epidemiologic studies. Until further data are available, therapy with neuroleptic agents should be administered cautiously in patients with a previously detected breast cancer. Caution is also advised in patients with preexisting hyperprolactinemia. Hyperprolactinemia may suppress hypothalamic gonadotrophin releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds; however, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.

Cases of sudden death, QT interval prolongation and ventricular arrhythmias including Torsade de Pointes have been reported in patients using haloperidol. Although cases have been reported even in the absence of predisposing factors, special caution is advised in treating patients with other QT- prolonging conditions (including electrolyte imbalance such as hypokalemia and hypomagnesemia), using QT- prolonging drugs, with underlying cardiac abnormalities, hypothyroidism and familial long QT syndrome. Consider periodic EKG assessment on these patients. Treatment should be discontinued and a cardiac evaluation should be considered if a patient develops signs or symptoms of ventricular arrhythmia.

Cases of sudden death, QT interval prolongation and ventricular arrhythmias including Torsade de Pointes have been reported in patients using haloperidol. Although cases have been reported even in the absence of predisposing factors, special caution is advised in treating patients with other QT- prolonging conditions (including electrolyte imbalance such as hypokalemia and hypomagnesemia), using QT- prolonging drugs, with underlying cardiac abnormalities, hypothyroidism and familial long QT syndrome. Consider periodic EKG assessment on these patients. Treatment should be discontinued and a cardiac evaluation should be considered if a patient develops signs or symptoms of ventricular arrhythmia.

Nateglinide is primarily metabolized in the liver to both pharmacologically active and inactive substances. Patients with impaired liver function may be exposed to higher concentrations of nateglinide and its associated metabolites. Higher serum drug levels, in addition to diminished gluconeogenic capacity secondary to hepatic insufficiency, may increase the potential for severe hypoglycemic episodes. Therapy with nateglinide should be administered cautiously in patients with liver disease. Dosage adjustments may be necessary in moderate to severe hepatic impairment, although clinical data are lacking.

Haloperidol appears to be primarily converted in the liver to several metabolites, one of which is believed to be pharmacologically active. The metabolites and approximately 1% of the parent drug are excreted in the urine. Patients with impaired renal and/or hepatic function may be at greater risk for adverse effects due to drug and metabolite accumulation. Therapy with haloperidol should be administered cautiously in such patients. Lower initial dosages and slower titration may be appropriate.

Cases of sudden death, QT interval prolongation and ventricular arrhythmias including Torsade de Pointes have been reported in patients using haloperidol. Although cases have been reported even in the absence of predisposing factors, special caution is advised in treating patients with other QT- prolonging conditions (including electrolyte imbalance such as hypokalemia and hypomagnesemia), using QT- prolonging drugs, with underlying cardiac abnormalities, hypothyroidism and familial long QT syndrome. Consider periodic EKG assessment on these patients. Treatment should be discontinued and a cardiac evaluation should be considered if a patient develops signs or symptoms of ventricular arrhythmia.

Hypoglycemia may commonly occur during treatment with insulin and/or oral hypoglycemic agents. Care should be taken in patients who may be particularly susceptible to the development of hypoglycemic episodes during the use of these drugs, including those who are debilitated or malnourished, those with defective counterregulatory mechanisms (e.g., autonomic neuropathy and adrenal or pituitary insufficiency), and those receiving beta-adrenergic blocking agents.

The use of antipsychotics has been associated with events of leukopenia, neutropenia and agranulocytosis. Possible risk factors include preexisting low white blood cell count, and history of drug induced leukopenia/neutropenia. Patients with these risk factors should have complete blood count monitored frequently during the first few months of therapy. Patients should also be monitored for any signs or symptoms of infection. Treatment should be discontinued in any patient who develops a sore throat, fever, stomatitis, or other signs of infection along with a low WBC count or severe neutropenia (ANC < 1000/mm3).

Hypoglycemia may commonly occur during treatment with insulin and/or oral hypoglycemic agents. Care should be taken in patients who may be particularly susceptible to the development of hypoglycemic episodes during the use of these drugs, including those who are debilitated or malnourished, those with defective counterregulatory mechanisms (e.g., autonomic neuropathy and adrenal or pituitary insufficiency), and those receiving beta-adrenergic blocking agents.

Haloperidol appears to be primarily converted in the liver to several metabolites, one of which is believed to be pharmacologically active. The metabolites and approximately 1% of the parent drug are excreted in the urine. Patients with impaired renal and/or hepatic function may be at greater risk for adverse effects due to drug and metabolite accumulation. Therapy with haloperidol should be administered cautiously in such patients. Lower initial dosages and slower titration may be appropriate.

Antipsychotic and neuroleptic drugs can lower the seizure threshold and trigger seizures in a dose-dependent manner. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Therapy with these drugs should be administered cautiously in patients with a history of seizures or other predisposing factors, such as head trauma, CNS abnormalities, and alcoholism.

Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs; the syndrome consists of potentially irreversible, involuntary, dyskinetic movements. The risk appears highest in older patients (particularly older women) but it is not possible to predict which patients are likely to develop TD; whether antipsychotic drugs differ in their potential to cause TD is unknown. The risk of TD and the likelihood that it will become irreversible increase with the duration of therapy and the total cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low dosages; it may also occur after discontinuation of therapy. TD may remit (partially or completely) upon discontinuation of antipsychotic therapy, although antipsychotic therapy itself may suppress (or partially suppress) signs/symptoms of TD, possibly masking the underlying process; the effect of symptomatic suppression on the long-term course of TD is unknown. In patients with preexisting drug-induced TD, initiating or increasing the dosage of antipsychotic therapy may temporarily mask the symptoms of TD but could eventually worsen the condition. In patients requiring chronic therapy, the lowest dose and shortest duration of therapy producing a satisfactory clinical response are recommended; the need for continued therapy should be reassessed periodically. If signs/symptoms of TD occur during antipsychotic therapy, discontinuation of the offending agent should be considered; however, some patients may require treatment despite the presence of TD.

Neuroleptic agents may cause hypotension (including orthostatic hypotension) and associated reflex tachycardia, syncope or dizziness, particularly during initiation of therapy or rapid escalation of dosage. Tolerance to the hypotensive effects often develops after a few doses to a few months. Rarely, fatal cardiac arrest has occurred secondary to severe hypotension. Therapy with neuroleptic agents should be administered cautiously in patients with conditions that would predispose them to hypotension, such as hypovolemia or dehydration (e.g., due to severe diarrhea or vomiting). In addition, neuroleptic agents can interfere with the body's ability to regulate core body temperature, occasionally producing hyperthermia during strenuous exercise, exposure to hot weather, and concomitant treatment with anticholinergic medications. Patients who are dehydrated may be particularly susceptible.