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 ).

DOSAGE AND ADMINISTRATION Haloperidol decanoate injection, 50 mg (base)/mL and haloperidol decanoate injection, 100 mg (base)/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 (base)/mL and haloperidol decanoate injection, 100 mg (base)/mL are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients must 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 (base)/mL or haloperidol decanoate injection, 100 mg (base)/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 10-15 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. HALOPERIDOL DECANOATE, USP DOSING RECOMMENDATIONS Patients Monthly 1 st Month Maintenance Stabilized on low daily oral doses (up to 10 mg/d …

3 DOSAGE FORMS AND STRENGTHS • Haloperidol decanoate injection, 50 mg/mL is a clear colorless/pink to yellow amber oily liquid, free from visible foreign material, in a single-dose vial. • Haloperidol decanoate injection, 250 mg/5 mL is a clear colorless/pink to yellow amber oily liquid, free from visible foreign material, in a multiple-dose vial. • Haloperidol decanoate injection, 100 mg/mL is a clear colorless/pink to yellow amber oily liquid, free from visible foreign material, in a single-dose vial. • Haloperidol decanoate injection, 500 mg/5 mL is a clear colorless/pink to yellow amber oily liquid, free from visible foreign material, in a multiple-dose vial. • Haloperidol decanoate injection, 50 mg/mL in single-dose vials ( 3 ). • Haloperidol decanoate injection, 250 mg/5 mL in multiple-dose vials ( 3 ). • Haloperidol decanoate injection, 100 mg/mL in single-dose vials ( 3 ). • Haloperidol decanoate injection, 500 mg/5 mL in multiple-dose vials ( 3 ).

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 is contraindicated in patients with: Severe toxic central nervous system depression or comatose states from any cause. Hypersensitivity to this drug – hypersensitivity reactions have included anaphylactic reaction and angioedema (see WARNINGS, Hypersensitivity Reactions and ADVERSE REACTIONS). Parkinson's disease (see WARNINGS, Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies). Dementia with Lewy bodies (see WARNINGS, Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies).

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: WARNINGS, Increased mortality in Elderly Patients with Dementia-Related Psychosis WARNINGS, Cardiovascular Effects WARNINGS, Tardive Dyskinesia WARNINGS, Neuroleptic Malignant Syndrome WARNINGS, Hypersensitivity Reactions WARNINGS, Falls WARNINGS, Combined Use of Haloperidol and Lithium WARNINGS, General PRECAUTIONS, Leukopenia, Neutropenia, and Agranulocytosis PRECAUTIONS, Other PRECAUTIONS, Usage in Pregnancy 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. The data described below reflect exposure to haloperidol in 410 patients who participated in 13 clinical trials with haloperidol decanoate (15 to 500 mg/month) in the treatment of schizophrenia or schizoaffective disorder. These clinical trials comprised: 1 double-blind, active comparator-controlled trial with fluphenazine decanoate. 2 trials comparing the decanoate formulation to oral haloperidol. 9 open-label trials. 1 dose-response trial. The most common adverse reactions in haloperidol decanoate-treated patients in the double-blind, active comparator-controlled clinical trial with fluphenazine decanoate (≥5%) were: Parkinsonism, and oculogyric crisis. Adverse Reactions Reported at ≥1% Incidence in a Double-Blind Active Comparator-Controlled Clinical Trial Adverse reactions occurring in 1% of haloperidol decanoate-treated patients in a double-blind, clinical trial with the active comparator fluphenazine decanoate are shown in Table 1. Table 1 . Adverse Reactions Reported by ≥1% of Haloperidol Decanoate-treated Patients in a Double- Blind Active Comparator-Controlled Clinical Trial with Fluphenazine Decanoate a Precise incidence for extrapyramidal disorder cannot be determined; reporting rates of some individual symptoms of extrapyramidal disorder are lower for haloperidol decanoate than for the active comparator, but the terms are included here because the events are considered associated with the drug System/Organ Class Adverse Reaction Haloperidol decanoate (n=36) % Fluphenazine decanoate (n=36) % Gastrointestinal Disorders Abdominal pain 2.8 0 Nervous System Disorders Extrapyramidal disorder a : Parkinsonism 30.6 44.4 Oculogyric crisis 5.6 0 Akinesia 2.8 22.2 Akathisia 2.8 13.9 Tremor 2.8 0 Headache 2.8 0 Additional Adverse Reactions Reported in Double-Blind, Comparator, Open-Label and Dose-Response Clinical Trials Additional adverse reactions that are listed below were reported by haloperidol decanoate-treated patients in comparator, open-label, and dose-response clinical trials, or at <1% incidence in a double-blind, active comparator-controlled clinical trial with fluphenazine decanoate. Cardiac Disorders: Tachycardia Endocrine Disorders: Hyperprolactinemia Eye Disorders: Vision blurred Gastrointestinal Disorders: Constipation, Dry mouth, Salivary hypersecretion General Disorders and Administration Site Conditions: Injection site reaction Investigations: Weight increased Musculoskeletal and Connective Tissue Disorders: Muscle rigidity Nervous System Disorders: Dyskinesia, Dystonia, Cogwheel rigidity, Hypertonia, Masked Facies, Sedation, Somnolence Reproductive System and Breast Disorders: Erectile dysfunction Adverse Reactions Identified in Clinical Trials with Haloperidol (Non-Decanoate Formulations) The adverse reactions listed below were identified with non-decanoate formulations, and reflect exposure to the active moiety haloperidol in the following: 284 patients who participated in 3 double-blind, placebo-controlled clinical trials with haloperidol (injection or oral formulation, 2 to 20 mg/day); two trials were in the treatment of schizophrenia and one in the treatment of bipolar disorder. 1295 patients who …

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 QTc interval-prolongation has been observed during haloperidol treatment, caution is advised when prescribing to a patient with QT-prolongation conditions or to patients receiving medications known to prolong the QTc-interval (see WARNINGS, Cardiovascular Effects ). Examples include (but are not limited to): Class 1A antiarrhythmics (e.g., procainamide, quinidine, disopyramide); Class 3 antiarrhythmics (e.g., amiodarone, sotalol); and other drugs such as citalopram, erythromycin, levofloxacin, methadone, and ziprasidone. Caution is advised when Haloperidol decanoate is used in combination with drugs known to cause electrolyte imbalance (e.g., diuretics or corticosteroids) because hypokalemia, hypomagnesemia, and hypocalcemia are risk factors for QT prolongation. As with other antipsychotic agents, it should be noted that haloperidol may be capable of potentiating CNS depressants such as anesthetics, opioids, and alcohol. Pharmacokinetic Interactions Drugs that May Increase Haloperidol Decanoate Plasma Concentrations Haloperidol is metabolized by several routes. The major pathways are glucuronidation and ketone reduction. The cytochrome P450 enzyme system is also involved, particularly CYP3A4 and, to a lesser extent, CYP2D6. Inhibition of these routes of metabolism by another drug or a decrease in CYP2D6 enzyme may result in increased haloperidol concentrations. The effect of CYP3A4 inhibition and of decreased CYP2D6 enzyme activity may be additive. The haloperidol plasma concentrations increased when a CYP3A4 and/or CYP2D6 inhibitor was coadministered with haloperidol. Examples include: CYP3A4 inhibitors – alprazolam; itraconazole, ketoconazole, nefazodone, ritonavir. CYP2D6 inhibitors – chlorpromazine; promethazine; quinidine; paroxetine, sertraline, venlafaxine. Combined CYP3A4 and CYP2D6 inhibitors – fluoxetine, fluvoxamine; ritonavir. Buspirone. Increased haloperidol plasma concentrations may result in an increased risk of adverse events, including QTc interval prolongation (see WARNINGS – Cardiovascular Effects ). Increases in QTc have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It is recommended that patients who take haloperidol concomitantly with such medicinal products be monitored for signs or symptoms of increased or prolonged pharmacologic effects of haloperidol, and the Haloperidol decanoate dose be decreased as deemed necessary. Valproate : Sodium valproate, a drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations. Drugs that May Decrease Haloperidol Plasma Concentrations Coadministration of haloperidol with potent enzyme inducers of CYP3A4 may gradually decrease the plasma concentrations of haloperidol to such an extent that efficacy may be reduced. Examples include (but are not limited to: carbamazepine, phenobarbital, phenytoin, rifampin, St John's Wort ( Hypericum, perforatum ). Rifampin: In a study of 12 patients with schizophrenia 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 patients with schizophrenia treated with oral haloperidol and rifampin, discontinuation of rifampin produced a mean 3.3-fold increase in haloperidol concentrations. Carbamazepine: In a study in 11 patients with schizophrenia coadministered haloperidol and increasing doses of carbamazepine, haloperidol plasma concentrations decreased linearly with increasing carbamazepine concentrations. During combination treatment with inducers of CYP3A4, it is recommended that patients be mo …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Neonates exposed to haloperidol decanoate injection during the third trimester of pregnancy may develop extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and decreased feeding) ( 8.1 ). Lactation: Monitor breastfed infants for excessive sedation, irritability, poor feeding, abnormal muscle movements, and tremors ( 8.2 ). 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. 8.2 Lactation Risk Summary Literature reports suggest that haloperidol is detected in human milk of haloperidol-treated mothers with a relative infant dose ranging from 2% to 12%. Haloperidol has also been detected in the plasma and urine of breastfed infants. There has been a report of lethargy, poor feeding, and slowing of motor movements in an infant exposed to haloperidol through human milk. Haloperidol may increase prolactin levels in some patients which can lead to galactorrhea. Monitor infants exposed to haloperidol decanoate injection via human milk for excessive sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle move …

12.1 Mechanism of Action The mechanism of action of haloperidol decanoate injection for the treatment of schizophrenia in adults is unclear. However, its effect in schizophrenia could be mediated through its activity as an antagonist at central dopamine type 2 receptors. Haloperidol also binds to alpha-1 adrenergic receptors, but with lower affinity, and displays minimal binding to muscarinic cholinergic and histaminergic (H 1 ) receptors.

11 DESCRIPTION Haloperidol decanoate, USP is the decanoate ester of the butyrophenone, haloperidol. 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, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate, is: The molecular formula is C 31 H 41 CIFNO 3 and has a molecular weight of 530.12. Haloperidol decanoate, USP is almost insoluble in water (0.01 mg/mL), but is soluble in most organic solvents. Each mL of Haloperidol decanoate injection, 50 mg/mL for IM injection contains 50 mg haloperidol (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 injection, 100 mg/mL for IM injection contains 100 mg haloperidol (present as haloperidol decanoate, USP 141.04 mg) in a sesame oil vehicle, with 1.2% (w/v) benzyl alcohol as a preservative. Haloperidol decanoate, USP

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 specic antidote, treatment is primarily supportive. Dialysis is not recommended in the treatment of overdose because it removes only very small amounts of haloperidol. 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 must 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 QTc-interval prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222).

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.)

HOW SUPPLIED Haloperidol Decanoate Injection is clear, slightly viscous, colorless to pink or amber solution supplied as follows: Haloperidol Decanoate Injection 50 mg for IM injection, 50 mg haloperidol as 70.52 mg per mL haloperidol decanoate. Haloperidol Decanoate Injection 100 mg for IM injection, 100 mg haloperidol as 141.04 mg per mL haloperidol decanoate. NDC No. Strength Size 70069- 030 -03 50 mg/mL 1 mL fill in 1 mL Ampule, in packages of 3 70069- 030 -05 1 mL fill in 1 mL Ampule, in packages of 5 70069- 031 -05 100 mg/mL 1 mL fill in 1 mL Ampule, in packages of 5 70069- 381 -01 50 mg/mL 1 mL fill in 2 mL Single-Dose Vial, in packages of 1 70069- 381 -10 1 mL fill in 2 mL Single-Dose Vial, in packages of 10 70069- 382 -05 250 mg/5mL (50 mg/mL) 5 mL fill in 5 mL Multiple-Dose Vial, in packages of 5 70069- 382 -01 5 mL fill in 5 mL Multiple-Dose Vial, in package of 1 70069- 383 -01 100 mg/mL 1 mL fill in 2 mL Single-Dose Vial, in packages of 1 70069- 383 -05 1 mL fill in 2 mL Single-Dose Vial, in packages of 5 70069- 383 -10 1 mL fill in 2 mL Single-Dose Vial, in packages of 10 70069- 384 -05 500 mg/5mL (100 mg/mL) 5 mL fill in 5 mL Multiple-Dose Vial, in packages of 5 70069- 384 -01 5 mL fill in 5 mL Multiple-Dose Vial, in package of 1 Store at 20o to 25oC (68o to 77oF); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate or freeze. Protect from Light. Keep out of reach of children. For Product Inquiry call 1-800-417-9175. Manufactured for: Somerset Therapeutics, LLC Hollywood, FL 33024 Made in India Code No.: KR/DRUGS/KTK/28/289/97 PSSO0398 ST-HAD/P/05 Revised: August 2021