HALDOL DECANOATE (haloperidol decanoate injection) is the decanoate ester of haloperidol, for intramuscular use. Haloperidol is a typical antipsychotic. The structural formula of haloperidol decanoate is 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl] piperidin-4-yl decanoate: The molecular formula is C 31 H 41 CIFNO 3 and has a molecular weight of 530.12. Haloperidol decanoate is almost insoluble in water (0.01 mg/mL) but is soluble in most organic solvents. Each mL of HALDOL DECANOATE contains: 50 mg of haloperidol (present as 70.5 mg of haloperidol decanoate) in a sesame oil vehicle (0.85 g/mL), with 15 mg/mL benzyl alcohol as a preservative. 100 mg of haloperidol (present as 141 mg of haloperidol decanoate) in a sesame oil vehicle (0.85 g/mL), with 15 mg/mL benzyl alcohol as a preservative. Chemical Structure

HALDOL DECANOATE is indicated for the treatment of schizophrenia in adults who were previously taking a stable dosage of an immediate-release oral haloperidol product. HALDOL DECANOATE is a typical antipsychotic indicated for the treatment of schizophrenia in adults who were previously taking a stable dosage of an immediate-release oral haloperidol product.

Injection: Haloperidol 50 mg/mL (present as haloperidol decanoate) is a clear, yellow to light amber viscous liquid, free from visible foreign material, in a single-dose ampule Haloperidol 100 mg/mL (present as haloperidol decanoate) is a clear, yellow to light amber viscous liquid, free from visible foreign material, in a single-dose ampule Injection: Haloperidol 50 mg/mL (present as haloperidol decanoate) in single-dose ampules. Haloperidol 100 mg/mL (present as haloperidol decanoate) in single-dose ampules.

Administer HALDOL DECANOATE by deep intramuscular injection every 4 weeks by a healthcare provider. Do not administer intravenously. For the recommended dosage, including the first recommended dose and the maintenance dosage, see the Dosage and Administration section. If schizophrenia symptoms worsen during dosage modification of HALDOL DECANOATE, consider administering an immediate-release oral haloperidol product in addition to HALDOL DECANOATE therapy

Recommended Dosage and Administration Administer HALDOL DECANOATE by deep intramuscular injection every 4 weeks by a health care professional. Do not administer HALDOL DECANOATE intravenously. When injecting HALDOL DECANOATE, use a 21-gauge needle. The maximum volume per injection site is 3 mL. Table 1 below describes the recommended dosage for HALDOL DECANOATE. The maximum recommended initial dose is 100 mg. If the calculated first recommended dose of HALDOL DECANOATE is greater than 100 mg, then administer two deep intramuscular injections as follows: 100 mg on the first day Remainder of the amount 3 to 7 days later. Table 1: HALDOL DECANOATE Recommended Dosage Population First Recommended Dose Maintenance Dosage Clinical experience with HALDOL DECANOATE at a dosage greater than 450 mg every 4 weeks has been limited. Adult patients less than 65 years old stabilized on ≤ 10 mg of daily immediate-release oral haloperidol with normal hepatic function. 10–15 times previous daily dose of immediate-release oral haloperidol. 10–15 times previous daily dose of immediate-release oral haloperidol administered every 4 weeks. The dosage may be increased by increments of 50 mg or less every 4 weeks until an optimal therapeutic effect is obtained. The typical effective dosage range is between 50 and 200 mg every 4 weeks. Adult patients less than 65 years old stabilized on ≤ 10 mg of daily immediate-release oral haloperidol with hepatic impairment OR Adult patients 65 years and older 10–15 times previous daily dose of immediate-release oral haloperidol. Consider starting at the low end of the dosing range . Adult patients less than 65 years old stabilized on >10 mg of daily immediate-release oral haloperidol 10–20 times previous daily dose of immediate-release oral haloperidol 10–15 times previous daily dose of immediate-release oral haloperidol administered every 4 weeks. The dosage may be increased by increments of 50 mg or less every 4 weeks until an optimal therapeutic effect is obtained

Recommended Supplemental Immediate-release Oral Haloperidol Therapy If schizophrenia symptoms worsen during dosage modification of HALDOL DECANOATE, consider administering an immediate-release oral haloperidol product in addition to HALDOL DECANOATE therapy

Preparation Instructions Visually inspect HALDOL DECANOATE for particulate matter and discoloration prior to administration. Do not use if the solution has debris or is not clear or not yellow to light amber in color. Instructions for breaking the ampule are as follows: Step 1 Figure A 1. Because some fluid may be in the top of the ampule, lightly tap the top of the ampule with your finger until all fluid moves to the bottom portion of the ampule before breaking the ampule. The colored ring and colored point of the ampule aid the placement of fingers while breaking the ampule . Step 2 Figure B 2. Hold the ampule between the thumb and index finger with the colored point facing you . Step 3 Figure C 3. Position the index finger of the other hand to support the neck of the ampule. Position the thumb of the same hand so that it covers the colored point and is parallel to the colored ring . Step 4 Figure D 4. With the thumb on the colored point and index fingers close together, apply firm pressure on the colored point and push away from your body, in the direction of the arrow, to snap the ampule open at the breaking level . Figure A Figure B Figure C Figure D

Sudden Death, Torsades de Pointes (TdP), and QTc Interval Prolongation: Avoid use of HALDOL DECANOATE in patients who are at risk of developing TdP. Avoid concomitant use of HALDOL DECANOATE with drugs that may increase risk of QTc interval prolongation or increase haloperidol exposure. Obtain ECG and serum electrolytes at baseline and during treatment as clinically indicated. Tachycardia and Hypotension: Monitor orthostatic vital signs. Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis: Use with caution in patients with schizophrenia who have risk factors for cerebrovascular adverse reactions. Tardive Dyskinesia: Discontinue treatment if clinically appropriate. Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely. Seizures: HALDOL DECANOATE is generally not recommended in patients receiving antiseizure drugs or who have a history of seizures or EEG abnormalities. If clinically, indicated, maintain patients taking HALDOL DECANOATE on adequate antiseizure therapy. Potential for Cognitive and Motor Impairment: Advise patients to not drive a motor vehicle or operate hazardous machinery until they are reasonably certain HALDOL DECANOATE does not impair their cognitive and motor functions. Risk of Encephalopathic Syndrome with Concomitant Use of Lithium: Monitor closely for early signs of neurological toxicity and discontinue HALDOL DECANOATE if such signs appear. Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing HALDOL DECANOATE if clinically significant decline in WBC occurs in absence of other causative factors. Discontinue HALDOL DECANOATE in patients with clinically significant neutropenia or an absolute neutrophile count of <1,000/mm 3. Hyperprolactinemia: Elevated prolactin levels may occur during acute and chronic use

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. In an analysis of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, the risk of death in antipsychotic drug-treated patients was 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the incidence of death in antipsychotic drug-treated patients was about 4.5%, compared to an incidence of about 2.6% in placebo-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. HALDOL DECANOATE is not approved for the treatment of patients with dementia-related psychosis

Sudden Death, Torsades de Pointes, and QTc Interval Prolongation Cases of sudden death, torsades de pointes (TdP) and QTc interval prolongation have been reported in haloperidol-treated patients . Cases have been reported even in the absence of predisposing factors. Higher than recommended haloperidol dosages were associated with a higher risk of TdP and QTc interval prolongation. Avoid use of HALDOL DECANOATE in patients who are at significant risk of developing TdP including those with congenital long QT syndrome, uncontrolled or significant cardiac disease, recent myocardial infarction, ischemic cardiomyopathy, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. Avoid the concomitant use of HALDOL DECANOATE with drugs that may increase the risk of the QTc interval prolongation or increase haloperidol exposure. Assess the QTc interval via an ECG at baseline, and during treatment as clinically indicated. Obtain serum electrolytes (including potassium, calcium, phosphorus, and magnesium) at baseline and during treatment as clinically indicated, and correct electrolyte abnormalities

Tachycardia and Hypotension Tachycardia and hypotension (including orthostatic hypotension) have been reported in patients treated with haloperidol . Orthostatic vital signs should be monitored in patients who are at risk for hypotension (e.g., geriatric patients, patients with dehydration, hypovolemia, and concomitantly treated with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. Should hypotension occur and a vasopressor be required, epinephrine must not be used since HALDOL DECANOATE may block its vasopressor activity, and paradoxically lower blood pressure. Instead, metaraminol, phenylephrine or norepinephrine should be used

Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials, elderly patients with dementia-related psychosis treated with antipsychotics had an increased risk of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) including fatalities, compared to those treated with placebo. The mechanism for this increased risk is not known. HALDOL DECANOATE is not approved for the treatment of patients with dementia-related psychosis. HALDOL DECANOATE should be used with caution in patients with schizophrenia who have risk factors for cerebrovascular adverse reactions

Tardive Dyskinesia Tardive dyskinesia (TD) may develop in patients treated with antipsychotic drugs, including HALDOL DECANOATE . TD can develop after a relatively brief treatment period at low dosages and may also occur after discontinuation of treatment. If antipsychotic treatment is discontinued, TD may partially or completely remit. Antipsychotic treatment, however, may suppress or partially suppress the signs and symptoms of TD and may mask the underlying process. The effect that symptomatic suppression has upon the long-term course of TD is unknown. The TD risk in patients treated with antipsychotic drugs appears to be highest among the elderly, especially elderly women, but it is not possible to predict, which patients are likely to develop TD. The TD risk and the likelihood that TD will become irreversible increase with the duration of antipsychotic drug treatment and the cumulative dosage. In patients who require chronic antipsychotic treatment, use the lowest dosage and the shortest duration of treatment that produces a satisfactory clinical response. Periodically reassess the need for continued treatment. If signs and symptoms of TD appear in HALDOL DECANOATE-treated patients, consider drug discontinuation. However, some patients may require HALDOL DECANOATE treatment despite the presence of TD

Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with the use of antipsychotic drugs . Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability, and additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue HALDOL DECANOATE and provide intensive symptomatic treatment and monitoring

Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies Patients with Parkinson's disease or Dementia with Lewy bodies may experience increased sensitivity to haloperidol. Manifestations of this increased sensitivity include severe extrapyramidal symptoms (e.g., tremor, rigidity, bradykinesia), confusion, sedation, and falls. HALDOL DECANOATE is contraindicated in patients with Dementia with Lewy bodies and in patients with Parkinson's disease

Seizures HALDOL DECANOATE may lower the seizure threshold. HALDOL DECANOATE is generally not recommended in patients receiving antiseizure drugs or have a history of seizures or EEG abnormalities. If clinically indicated, maintain patients taking HALDOL DECANOATE on adequate antiseizure therapy

Hypersensitivity Reactions There have been postmarketing reports of hypersensitivity reactions with haloperidol including anaphylactic reaction, angioedema, dermatitis exfoliative, hypersensitivity vasculitis, rash, urticaria, face edema, laryngeal edema, bronchospasm, and laryngospasm . HALDOL DECANOATE is contraindicated in patients with known hypersensitivity to haloperidol or any components of HALDOL DECANOATE

Falls Antipsychotics, including HALDOL DECANOATE, may cause somnolence, orthostatic hypotension, motor instability and sensory abnormality, which may lead to falls and, consequently, fractures and other injuries. If patients have a condition (or take concomitant drugs) that could exacerbate these effects, complete fall risk assessments when initiating HALDOL DECANOATE treatment and periodically during long-term treatment

Potential for Cognitive and Motor Impairment HALDOL DECANOATE may impair judgement, thinking, or motor skills. Inform patients of the risk and advise them to not drive a motor vehicle or operate hazardous machinery until they are reasonably certain that treatment with HALDOL DECANOATE does not impair their cognitive and motor functions

Risk of Encephalopathic Syndrome with Concomitant Use of Lithium An encephalopathic syndrome, characterized by weakness, lethargy, fever, tremulousness, confusion, extrapyramidal symptoms, leukocytosis, and elevated serum enzymes (AST, ALT, GGT, alkaline phosphatase, CK, and LDH), BUN, and fasting blood sugar, followed by irreversible brain damage has occurred in a few patients treated with concomitant haloperidol and lithium. Monitor patients who concomitantly use HALDOL DECANOATE and lithium closely for early signs of neurological toxicity, and discontinue HALDOL DECANOATE or both HALDOL DECANOATE and lithium promptly if such signs appear

Leukopenia, Neutropenia, and Agranulocytosis Leukopenia, neutropenia and agranulocytosis (including fatal cases) have been reported during treatment with antipsychotic drugs, including HALDOL DECANOATE . Possible risk factors for antipsychotic drug-associated leukopenia and neutropenia include pre-existing low WBC and history of drug-induced leukopenia and neutropenia. Perform frequent complete blood count (CBC) monitoring during the first few months of HALDOL DECANOATE therapy in patients with a history of a clinically significant low WBC, drug-induced leukopenia or neutropenia. Consider discontinuing HALDOL DECANOATE in patients who have a clinically significant decline in their WBC in the absence of other causative factors. Discontinue HALDOL DECANOATE in patients with clinically significant neutropenia or an absolute neutrophil count of <1,000/mm 3 and monitor closely until the neutropenia resolves

Hyperprolactinemia Antipsychotic drugs elevate prolactin levels during acute and chronic use and may result in galactorrhea, amenorrhea, gynecomastia, and impotence which have been reported with antipsychotic drugs . Published epidemiologic studies have shown inconsistent results regarding the potential association between hyperprolactinemia and breast cancer

Risk of Severe Neurotoxicity in Patients with Thyrotoxicosis Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with thyrotoxicosis who are also receiving antipsychotic drugs, including HALDOL DECANOATE.

Drugs that Prolong QTc Interval: Avoid concomitant use with HALDOL DECANOATE. See full prescribing information for additional clinically significant drug interactions with HALDOL DECANOATE

Drugs that Prolong the QTc Interval Avoid concomitant use of HALDOL DECANOATE with other drugs with a known potential to prolong the QTc interval. If concomitant use cannot be avoided : Obtain ECGs when initiating and during concomitant use as clinically indicated. Obtain serum electrolytes (including potassium, calcium, phosphorus, and magnesium) when initiating and during concomitant use as clinically indicated. QTc interval prolongation has been observed with HALDOL DECANOATE treatment. Concomitant use of HALDOL DECANOATE with other products that prolong the QTc interval may result in a greater increase in the QTc interval, and adverse reactions associated with QTc interval prolongation, including torsade de pointes, other serious arrythmias, and sudden death

Other Clinically Significant Drug Interactions Table 3 describes other clinically significant drug interactions of HALDOL DECANOATE. Table 3: Other Clinically Significant Drugs Interactions See www.fda.gov/CYPandTransporterInteractingDrugs for examples of CYP3A4 and/or CYP2D6 inhibitors, CYP3A4 inducers, and CYP2D6 substrates. CNS Depressants Clinical Impact Haloperidol may potentiate CNS depressants. Prevention or Management Avoid concomitant use of HALDOL DECANOATE with CNS depressants such as anesthetics, opioids, and alcohol. CYP3A4 and/or CYP2D6 Inhibitors Clinical Impact CYP3A4 and/or CYP2D6 inhibitors increase haloperidol exposure (haloperidol is a CYP3A4 and CYP2D6 substrate) . Concomitant use of HALDOL DECANOATE and CYP3A4 and/or CYP2D6 inhibitors may increase the risk of haloperidol-associated adverse reactions. Prevention or Management Monitor for signs or symptoms of increased or prolonged pharmacologic effects of haloperidol. Decrease the dosage of HALDOL DECANOATE as clinically necessary. CYP3A4 Inducers Clinical Impact CYP3A4 inducers decrease haloperidol exposure (haloperidol is a CYP3A4 substrate) . Concomitant use of HALDOL DECANOATE with CYP3A4 inducers may reduce the effectiveness of HALDOL DECANOATE. Prevention or Management Monitor patients and if necessary, increase the dosage of HALDOL DECANOATE. CYP2D6 Substrates Clinical Impact Haloperidol is a CYP2D6 inhibitor. Plasma concentrations of CYP2D6 substrates may increase when they are concomitantly administered with HALDOL DECANOATE. Prevention or Management Monitor plasma concentrations of the CYP2D6 substrate, if possible. Consider reducing the dosage of the CYP2D6 substrate, if necessary. Refer to the Prescribing Information of the CYP2D6 substrate. Dopaminergic Drugs Clinical Impact Haloperidol may antagonize the effects of levodopa, dopamine agonists, and other drugs intended to increase dopamine levels. Prevention or Management HALDOL DECANOATE is contraindicated in patients with Parkinson's disease and dementia with Lewy bodies. For conditions other than Parkinson's disease and dementia with Lewy bodies, when possible, avoid concomitant use of HALDOL DECANOATE with dopaminergic drugs . Anticholinergic Drugs Clinical Impact The healthcare provider should keep in mind the possible increase in intraocular pressure when anticholinergic drugs are administered concomitantly with HALDOL DECANOATE. Prevention or Management Monitor and manage patients as clinically appropriate. Lithium Clinical Impact Concomitant use of HALDOL DECANOATE with lithium may cause an encephalopathic syndrome followed by irreversible brain damage . Prevention or Management Monitor patients who concomitantly use HALDOL DECANOATE with lithium closely for early signs of neurological toxicity, and discontinue HALDOL DECANOATE or both HALDOL DECANOATE and lithium promptly if such signs appear.