Haloperidol Decanoate

Amneal-Agila, LLC

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING
• HALOPERIDOL DECANOATE DESCRIPTION
• CLINICAL PHARMACOLOGY
• HALOPERIDOL DECANOATE INDICATIONS AND USAGE
• HALOPERIDOL DECANOATE CONTRAINDICATIONS
• WARNINGS
  • Tardive Dyskinesia
  • Neuroleptic Malignant Syndrome (NMS)
  • Combined Use of Haloperidol and Lithium
  • General
• PRECAUTIONS
  • Leukopenia, Neutropenia, and Agranulocytosis
  • Other
  • Information for Patients
  • Drug Interactions
  • Pharmacodynamic Interactions
  • Pharmacokinetic Interactions
  • Carcinogenesis, Mutagenesis, and Impairment of Fertility
  • Usage in Pregnancy
  • Nursing Mothers
  • Pediatric Use
  • Geriatric Use
• HALOPERIDOL DECANOATE ADVERSE REACTIONS
• OVERDOSAGE
• HALOPERIDOL DECANOATE DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

HALOPERIDOL DECANOATE DESCRIPTION

Haloperidol decanoate, USP is the decanoate ester of the butyrophenone, haloperidol, USP. It has a markedly extended duration of effect. It is available in sesame oil in sterile form for intramuscular (IM) injection. The structural formula of haloperidol decanoate, USP, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate, is:

Haloperidol decanoate, USP is almost insoluble in water (0.01 mg/mL), but is soluble in most organic solvents.

Each mL of haloperidol decanoate, USP 50 mg/mL for IM injection contains 50 mg haloperidol, USP (present as haloperidol decanoate, USP 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative.

Each mL of haloperidol decanoate, USP 100 mg/mL for IM injection contains 100 mg haloperidol, USP (present as haloperidol decanoate, USP 141.04 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative.

CLINICAL PHARMACOLOGY

Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL are the long-acting forms of haloperidol. The basic effects of haloperidol decanoate are no different from those of haloperidol with the exception of duration of action. Haloperidol blocks the effects of dopamine and increases its turnover rate; however, the precise mechanism of action is unknown.

Administration of haloperidol decanoate in sesame oil results in slow and sustained release of haloperidol. The plasma concentrations of haloperidol gradually rise, reaching a peak at about 6 days after the injection, and falling thereafter, with an apparent half-life of about 3 weeks. Steady-state plasma concentrations are achieved after the third or fourth dose. The relationship between dose of haloperidol decanoate and plasma haloperidol concentration is roughly linear for doses below 450 mg. It should be noted, however, that the pharmacokinetics of haloperidol decanoate following intramuscular injections can be quite variable between subjects.

HALOPERIDOL DECANOATE INDICATIONS AND USAGE

Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL are indicated for the treatment of schizophrenic patients who require prolonged parenteral antipsychotic therapy.

HALOPERIDOL DECANOATE CONTRAINDICATIONS

Since the pharmacologic and clinical actions of haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL are attributed to haloperidol, USP as the active medication, Contraindications, Warnings and additional information are those of haloperidol, USP, modified only to reflect the prolonged action.

Haloperidol, USP is contraindicated in severe toxic central nervous system depression or comatose states from any cause and in individuals who are hypersensitive to this drug or have Parkinson’s disease.

WARNINGS

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Haloperidol Decanoate is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING).

Cardiovascular Effects

Cases of sudden death, QT-prolongation and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism and familial long QT-syndrome). HALOPERIDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY.

Tardive Dyskinesia

A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to ADVERSE REACTIONS .)

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Hyperpyrexia and heat stroke, not associated with the above symptom complex, have also been reported with haloperidol.

Combined Use of Haloperidol and Lithium

An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN and fasting blood sugar) followed by irreversible brain damage has occurred in a few patients treated with lithium plus haloperidol. A causal relationship between these events and the concomitant administration of lithium and haloperidol has not been established; however, patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear.

General

A number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including haloperidol. It has been postulated that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly.

Although not reported with haloperidol, decreased serum cholesterol and/or cutaneous and ocular changes have been reported in patients receiving chemically-related drugs.

PRECAUTIONS

Leukopenia, Neutropenia, and Agranulocytosis

Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including haloperidol decanoate. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of haloperidol decanoate should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm³) should discontinue haloperidol decanoate and have their WBC followed until recovery.

Other

Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL should be administered cautiously to patients:

• with severe cardiovascular disorders, because of the possibility of transient hypotension and/or precipitation of anginal pain. Should hypotension occur and a vasopressor be required, epinephrine should not be used since haloperidol may block its vasopressor activity, and paradoxical further lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should be used.
• receiving anticonvulsant medications, with a history of seizures, or with EEG abnormalities, because haloperidol may lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be concomitantly maintained.
• with known allergies, or with a history of allergic reactions to drugs.
• receiving anticoagulants, since an isolated instance of interference occurred with the effects of one anticoagulant (phenindione).

If concomitant antiparkinson medication is required, it may have to be continued after haloperidol decanoate injection, 50 mg/mL or haloperidol decanoate injection, 100 mg/mL is discontinued because of the prolonged action of haloperidol decanoate. If both drugs 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 haloperidol decanoate.

When haloperidol decanoate is used to control mania in cyclic disorders, there may be a rapid mood swing to depression.

Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic medication, including haloperidol.

Information for Patients

Haloperidol decanoate 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.

Drug Interactions

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 haloperidol treatment, caution is advised when prescribing to 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.

As with other antipsychotic agents, it should be noted that haloperidol 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 Decanoate

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.

When prolonged treatment (1 to 2 weeks) with enzyme-inducing drugs such as rifampin or carbamazepine is added to haloperidol 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 haloperidol dose should be adjusted, when necessary. After discontinuation of such drugs, it may be necessary to reduce the dosage of haloperidol.

Valproate

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

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella microsomal activation assay. Negative or inconsistent positive findings have been obtained in in vitro and in vivo studies of effects 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 less than optimal in all dose groups, reducing 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 20 times the usual daily human dose for chronic or resistant patients.

In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant patients, there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; at 20 times the same daily dose there was a statistically significant increase in pituitary gland neoplasia. 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.

Usage in Pregnancy

Pregnancy Category C. Rodents given up to 3 times the usual maximum human dose of haloperidol decanoate showed an increase in incidence of resorption, fetal mortality and pup mortality. No fetal abnormalities were observed.

Cleft palate has been observed in mice given oral haloperidol at 15 times the usual maximum human dose. Cleft palate in mice appears to be a nonspecific response to stress or nutritional imbalance as well as to a variety of drugs, and there is no evidence to relate this phenomenon to predictable human risk for most of these agents.

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 Effects

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 ).

HALOPERIDOL DECANOATE ADVERSE REACTIONS

Adverse reactions following the administration of haloperidol decanoate injection, 50 mg/mL or haloperidol decanoate injection, 100 mg/mL are those of haloperidol. Since vast experience has accumulated with haloperidol, the adverse reactions are reported for that compound as well as for haloperidol decanoate. As with all injectable medications, local tissue reactions have been reported with haloperidol decanoate.

Cardiovascular Effects

Tachycardia, hypotension and hypertension have been reported. QT prolongation and/or ventricular arrhythmias have also been reported, in addition to ECG pattern changes compatible with the polymorphous configuration of torsade de pointes, and may occur more frequently with high doses and in predisposed patients (see  WARNINGS and PRECAUTIONS ).

Cases of sudden and unexpected death have been reported in association with the administration of haloperidol. The nature of the evidence makes it impossible to determine definitively what role, if any, haloperidol played in the outcome of the reported cases. The possibility that haloperidol caused death cannot, of course, be excluded, but it is to be kept in mind that sudden and unexpected death may occur in psychotic patients when they go untreated or when they are treated with other antipsychotic drugs.

CNS Effects

Extrapyramidal Symptoms (EPS)

EPS during the administration of haloperidol have been reported frequently, often during the first few days of treatment. EPS can be categorized generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos and oculogyric crisis). While all can occur at relatively low doses, they occur more frequently and with greater severity at higher doses. The symptoms may be controlled with dose reductions or administration of antiparkinson drugs such as benztropine mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that persistent EPS have been reported; the drug may have to be discontinued in such cases.

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Withdrawal Emergent Neurological Signs

Generally, patients receiving short-term therapy experience no problems with abrupt discontinuation of antipsychotic drugs. However, some patients on maintenance treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of these cases the dyskinetic movements are indistinguishable from the syndrome described below under “Tardive Dyskinesia” except for duration. Although the long-acting properties of haloperidol decanoate provide gradual withdrawal, it is not known whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence of withdrawal emergent neurological signs.

Tardive Dyskinesia

As with all antipsychotic agents haloperidol has been associated with persistent dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may appear in some patients on long-term therapy with haloperidol decanoate or may occur after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear irreversible. The syndrome is characterized by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities and the trunk.

There is no known effective treatment for tardive dyskinesia; antiparkinson agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, this syndrome may be masked.

It has been reported that fine vermicular movement of the tongue may be an early sign of tardive dyskinesia and if the medication is stopped at that time the full syndrome may not develop.

Tardive Dystonia

Tardive dystonia, not associated with the above syndrome, has also been reported. Tardive dystonia is characterized by delayed onset of choreic or dystonic movements, is often persistent, and has the potential of becoming irreversible.

Other CNS Effects

Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic symptoms including hallucinations, and catatonic-like behavioral states which may be responsive to drug withdrawal and/or treatment with anticholinergic drugs.

Body as a Whole

Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with haloperidol. (See  WARNINGS for further information concerning NMS.)

Hematologic Effects

Reports have appeared citing the occurrence of mild and usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward lymphomonocytosis. Agranulocytosis has rarely been reported to have occurred with the use of haloperidol, and then only in association with other medication. (See PRECAUTIONS: Leukopenia, Neutropenia, and Agranulocytosis .)

Liver Effects

Impaired liver function and/or jaundice have been reported.

Dermatologic Reactions

Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair.

Endocrine Disorders

Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia.

Gastrointestinal Effects

Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting.

Autonomic Reactions

Dry mouth, blurred vision, urinary retention, diaphoresis and priapism.

Respiratory Effects

Laryngospasm, bronchospasm and increased depth of respiration.

Special Senses

Cataracts, retinopathy and visual disturbances.

Postmarketing Events

Hyperammonemia has been reported in a 5 ½ year old child with citrullinemia, an inherited disorder of ammonia excretion, following treatment with haloperidol.

OVERDOSAGE

While overdosage is less likely to occur with a parenteral than with an oral medication, information pertaining to haloperidol is presented, modified only to reflect the extended duration of action of haloperidol decanoate.

Manifestations

In general, the symptoms of overdosage would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. The extrapyramidal reactions would be manifested by muscular weakness or rigidity and a generalized or localized tremor, as demonstrated by the akinetic or agitans types, respectively. With accidental overdosage, hypertension rather than hypotension occurred in a two-year old child. The risk of ECG changes associated with torsade de pointes should be considered.

(For further information regarding torsade de pointes, please refer to ADVERSE REACTIONS .)

Treatment

Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered, and should be continued for several weeks, and then withdrawn gradually as extrapyramidal symptoms may emerge. ECG and vital signs should be monitored especially for signs of QT-prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures.

HALOPERIDOL DECANOATE DOSAGE AND ADMINISTRATION

Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate, USP. Furthermore, it is recommended that patients being considered for haloperidol decanoate, USP therapy have been treated with, and tolerate well, short-acting haloperidol, USP in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol, USP. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate, USP therapy can be supplemented with short-acting forms of haloperidol, USP.

The dose of haloperidol decanoate injection, 50 mg/mL or haloperidol decanoate injection, 100 mg/mL should be expressed in terms of its haloperidol, USP content. The starting dose of haloperidol decanoate, USP should be based on the patient’s age, clinical history, physical condition, and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed. For patients previously maintained on low doses of antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate, USP be 10 to 15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate.

Initial Therapy

Conversion from oral haloperidol to haloperidol decanoate, USP can be achieved by using an initial dose of haloperidol decanoate, USP that is 10 to 20 times the previous daily dose in oral haloperidol equivalents.

In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion.

In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol, USP has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections.

The initial dose of haloperidol decanoate, USP should not exceed 100 mg regardless of previous antipsychotic dose requirements. If, therefore, conversion requires more than 100 mg of haloperidol decanoate, USP as an initial dose, that dose should be administered in two injections, i.e. a maximum of 100 mg initially followed by the balance in 3 to 7 days.

Maintenance Therapy

The maintenance dosage of haloperidol decanoate, USP must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient.

Close clinical supervision is required during initiation and stabilization of haloperidol decanoate, USP therapy. Haloperidol decanoate, USP is usually administered monthly or every 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY ).

Clinical experience with haloperidol decanoate, USP at doses greater than 450 mg per month has been limited.

HOW SUPPLIED

Haloperidol Decanoate Injection, 50 mg/mL, 50 mg haloperidol, USP as 70.52 mg per mL haloperidol decanoate, USP in:

5 mL multiple dose vials (NDC 53150-422-01) packaged in cartons of five - NDC 53150-422-05
1 mL single dose vials (NDC 53150-415-01) packaged in cartons of ten - NDC 53150-415-10

Haloperidol Decanoate Injection, 100 mg/mL, 100 mg haloperidol as 141.04 mg per mL haloperidol decanoate. USP in:

5 mL multiple dose vials (NDC 53150-489-01) packaged in cartons of five – NDC 53150-489-05
1 mL single dose vials (NDC 53150-485-01) packaged in cartons of five – NDC 53150-485-05

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate or freeze.

Protect from light. Retain vial in carton until contents are used.

Manufactured by:
Agila Specialties Private Limited
Bangalore, India
Made in India

Distributed by:
Amneal-Agila, LLC
Glasgow, KY  42141

Rev. 01-2013

PRINCIPAL DISPLAY PANEL