Haloperidol Decanoate

1 INDICATIONS AND USAGE Haloperidol Decanoate Injection is indicated for the treatment of schizophrenia in adults who were previously taking a stable dosage of an immediate-release oral haloperidol product. Haloperidol Decanoate Injection 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 ( 1 ).

2 DOSAGE AND ADMINISTRATION Administer haloperidol decanoate injection by deep intramuscular injection every 4 weeks by a healthcare provider. Do not administer intravenously ( 2.1 ). For the recommended dosage, including the first recommended dose and the maintenance dosage, see the Dosage and Administration section ( 2.1 ). If schizophrenia symptoms worsen during dosage modification of haloperidol decanoate injection, consider administering an immediate-release oral haloperidol product in addition to haloperidol decanoate injection therapy ( 2.2 ). 2.1 Recommended Dosage and Administration Administer haloperidol decanoate injection by deep intramuscular injection every 4 weeks by a health care professional. Do not administer haloperidol decanoate injection intravenously. When injecting haloperidol decanoate injection, use a 21-gauge needle. The maximum volume per injection site is 3 mL. Table 1 below describes the recommended dosage for haloperidol decanoate injection. The maximum recommended initial dose is 100 mg. If the calculated first recommended dose of haloperidol decanoate injection 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: Haloperidol Decanoate Injection Recommended Dosage Population First Recommended Dose Maintenance Dosage 1 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 [see Use in Specific Populations (8.5 , 8.6) and Clinical Pharmacology (12.3) ]. 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. 1 Clinical experience with haloperidol decanoate injection at a dosage greater than 450 mg every 4 weeks has been limited. 2.2 Recommended Supplemental Immediate-release Oral Haloperidol Therapy If schizophrenia symptoms worsen during dosage modification of haloperidol decanoate injection, consider administering an immediate-release oral haloperidol product in addition to haloperidol decanoate injection therapy. 2.3 Preparation Instructions Visually inspect haloperidol decanoate injection for particulate matter and discoloration prior to administration. Do not use if the solution has debris or is not clear or not colorless to pink or amber in color.

5 WARNINGS AND PRECAUTIONS Sudden Death, Torsades de Pointes (TdP), and QTc Interval Prolongation: Avoid use of haloperidol decanoate injection in patients who are at risk of developing TdP. Avoid concomitant use of haloperidol decanoate injection 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 ( 5.2 ). Tachycardia and Hypotension: Monitor orthostatic vital signs ( 5.3 ). 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 ( 5.4 ). Tardive Dyskinesia: Discontinue treatment if clinically appropriate ( 5.5 ). Neuroleptic Malignant Syndrome (NMS): Immediately discontinue and monitor closely ( 5.6 ). Seizures: Haloperidol decanoate injection 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 haloperidol decanoate injection on adequate antiseizure therapy ( 5.8 ). Potential for Cognitive and Motor Impairment: Advise patients to not drive a motor vehicle or operate hazardous machinery until they are reasonably certain haloperidol decanoate injection does not impair their cognitive and motor functions ( 5.11 ). Risk of Encephalopathic Syndrome with Concomitant Use of Lithium: Monitor closely for early signs of neurological toxicity and discontinue haloperidol decanoate injection if such signs appear ( 5.12 ). 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 haloperidol decanoate injection if clinically significant decline in WBC occurs in absence of other causative factors. Discontinue haloperidol decanoate injection in patients with clinically significant neutropenia or an absolute neutrophile count of <1,000/mm 3 ( 5.13 ). Hyperprolactinemia: Elevated prolactin levels may occur during acute and chronic use ( 5.14 ). 5.1 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. Haloperidol decanoate injection is not approved for the treatment of patients with dementia-related psychosis [see Indications and Usage (1) ] . 5.2 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 [see Adverse Reactions (6.1 , 6.2) ] . 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 haloperidol decanoate injection 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, o…

4 CONTRAINDICATIONS Haloperidol decanoate injection is contraindicated in patients with: Severe toxic central nervous system depression or comatose states from any cause. Known hypersensitivity to haloperidol or any components of haloperidol decanoate injection. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with haloperidol [see Warnings and Precautions (5.9) and Adverse Reactions (6.2) ] . Parkinson's disease [see Warnings and Precautions (5.7) ]. Dementia with Lewy bodies [see Warnings and Precautions (5.7) ] . Severe toxic central nervous system depression or comatose states from any cause ( 4 ). Known hypersensitivity to haloperidol or any components of haloperidol decanoate injection ( 4 ). Parkinson's disease ( 4 , 5.7 , 6.1 ). Dementia with Lewy bodies ( 4 , 5.7 ).

7 DRUG INTERACTIONS Drugs that Prolong QTc Interval: Avoid concomitant use with haloperidol decanoate injection ( 7.1 ). See full prescribing information for additional clinically significant drug interactions with haloperidol decanoate injection ( 7.2 ). 7.1 Drugs that Prolong the QTc Interval Avoid concomitant use of haloperidol decanoate injection with other drugs with a known potential to prolong the QTc interval. If concomitant use cannot be avoided [see Warnings and Precautions (5.2) ] : 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 haloperidol decanoate injection treatment. Concomitant use of haloperidol decanoate injection 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 [see Warnings and Precautions (5.2) ]. 7.2 Other Clinically Significant Drug Interactions Table 3 describes other clinically significant drug interactions of haloperidol decanoate injection. Table 3: Other Clinically Significant Drugs Interactions 1 CNS Depressants Clinical Impact Haloperidol may potentiate CNS depressants. Prevention or Management Avoid concomitant use of haloperidol decanoate injection 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) [see Clinical Pharmacology (12.3) ]. Concomitant use of haloperidol decanoate injection 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 haloperidol decanoate injection as clinically necessary. CYP3A4 Inducers Clinical Impact CYP3A4 inducers decrease haloperidol exposure (haloperidol is a CYP3A4 substrate) [see Clinical Pharmacology (12.3) ]. Concomitant use of haloperidol decanoate injection with CYP3A4 inducers may reduce the effectiveness of haloperidol decanoate injection. Prevention or Management Monitor patients and if necessary, increase the dosage of haloperidol decanoate injection. CYP2D6 Substrates Clinical Impact Haloperidol is a CYP2D6 inhibitor. Plasma concentrations of CYP2D6 substrates may increase when they are concomitantly administered with haloperidol decanoate injection. 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 Haloperidol decanoate injection 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 haloperidol decanoate injection with dopaminergic drugs [see Warnings and Precautions (5.7) ] . Anticholinergic Drugs Clinical Impact The healthcare provider should keep in mind the possible increase in intraocular pressure when anticholinergic drugs are administered concomitantly with haloperidol decanoate injection. Prevention or Management Monitor and manage patients as clinically appropriate. Lithium Clinical Impact Concomitant use of haloperidol decanoate injection with lithium may cause an encephalopathic syndrome followed by irreversible brain damage [see Warnings and Precautions (5.12) ] . Preventi…

8.1 Pregnancy Risk Summary Available data from published epidemiologic studies of pregnant patients exposed to haloperidol have not established a drug-associated risk of major birth defects or miscarriage. Case reports of limb malformations in neonates have been reported in haloperidol-treated mothers; however, causal relationships were not established in these cases. There are risks to the pregnant patient from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide (see Clinical Considerations ) . Haloperidol decanoate injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and decreased feeding) following delivery (see Clinical Considerations ) . The estimated background risk of major birth defects and miscarriage in patients with schizophrenia is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk: There is risk to the pregnant patient from untreated schizophrenia, including increased risk of schizophrenia relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions: Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and decreased feeding have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. Transient neonatal dyskinesia has also been reported. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal, withdrawal, and dyskinesia symptoms and manage symptoms appropriately. Data Animal Data: Rats or rabbits administered oral haloperidol at doses of 0.5 to 7.5 mg/kg (approximately 0.2 to 7 times the maximum recommended human oral dose (MRHD) of 20 mg/day based on mg/m 2 body surface area) showed an increase in incidence of resorption, reduced fertility, delayed delivery, and pup mortality. No fetal abnormalities were observed at these doses in rats or rabbits. Cleft palate has been observed in mice administered oral haloperidol at a dose of 0.5 mg/kg, which is approximately 0.1 times the oral MRHD based on mg/m 2 body surface area.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Sudden Death, Torsades de Pointes, and QTc Interval Prolongation [see Warnings and Precautions (5.2) ] Tachycardia and Hypotension [see Warnings and Precautions (5.3) ] Tardive Dyskinesia [see Warnings and Precautions (5.5) ] Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.6) ] Seizures [see Warnings and Precautions (5.8) ] Hypersensitivity Reactions [see Warnings and Precautions (5.9) ] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.13) ] Hyperprolactinemia [see Warnings and Precautions (5.14) ] Risk of Severe Neurotoxicity in Patients with Thyrotoxicosis [see Warnings and Precautions (5.15) ] The most common adverse reactions (incidence ≥5%) were oculogyric crisis and parkinsonism ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals, Inc. at 1-888-808-5529 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions Identified in Clinical Trials with Haloperidol Decanoate Injection The data described below reflect exposure to 15 mg to 500 mg (1.7 times the maximum recommended dosage) of haloperidol decanoate injection monthly in 13 clinical trials of 410 adult patients with schizophrenia or an unapproved condition. These clinical trials comprised of: 1 double-blind, active comparator-controlled trial with fluphenazine decanoate (Trial 1). 2 trials comparing haloperidol decanoate injection to oral haloperidol (Trials 2 and 3). 9 open-label trials. 1 dose-response trial. The most common adverse reactions that occurred in ≥5% of haloperidol decanoate injection-treated patients in Trial 1 were Parkinsonism and oculogyric crisis. Adverse reactions that occurred in ≥1% of haloperidol decanoate injection-treated patients in Trial 1 are shown in Table 2. Trial 1 was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the haloperidol decanoate injection and fluphenazine decanoate treatment groups. Table 2: Adverse Reactions that Occurred in ≥1% of Haloperidol Decanoate Injection-treated Patients and Fluphenazine Decanoate-treated Patients in Trial a Haloperidol Decanoate Injection (n=36) Fluphenazine decanoate (n=36) Extrapyramidal disorder: Parkinsonism 31% 44% Oculogyric crisis 6% 0% Akinesia 3% 22% Akathisia 3% 14% Tremor 3% 0% Abdominal pain 3% 0% Headache 3% 0% a The study was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the haloperidol decanoate injection and the fluphenazine decanoate treatment groups. Less common adverse reactions (<1%) that occurred in Trial 1 and other adverse reactions that occurred in Trials 2 and 3, and open-label and dose-response clinical trials of haloperidol decanoate injection are listed below. Cardiac Disorders: Tachycardia Endocrine Disorders: Hyperprolactinemia Eye Disorders: Vision blurred Gastrointestinal Disorders: Constipation, Dry mouth, Salivary hypersecretion General Disorders and Administration Site Conditions: Weight increased, Injection site reaction Musculoskeletal and Connective Tissue Disorders: Muscle rigidity Nervous System Disorders: Dyskinesia, Dystonia, Cogwheel rigidity, Hypertonia, Masked facies, Sedation, Somnolence Reproductive System Disorders: Erectile dysfunction Adverse Reactions Identified in Clinical Trials with Immediate-Release Haloperidol Products Based on clinical trials with immediate-release haloperidol products that included 1,579 patients, the following adverse reactions were reported: Musculoskeletal and Connective Tissue Disorders: Torticollis, Trismus, Muscle twitching Nervous System Disorders:…