5Z

Patients with neutropenia should be carefully moni­ tored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. 45849F/Revised: September 2010 Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Fluphenazine Decanoate Injection, USP and have their WBC followed until recovery. FLUPHENAZINE DECANOATE Information for Patients INJECTION, USP Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. ADVERSE REACTIONS: Central Nervous System The side effects most frequently reported with phe­ nothiazine compounds are extrapyramidal symptoms including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyper­ reflexia. Muscle rigidity sometimes accompanied by hyperthermia has been reported following use of fluphenazine decanoate. Most often these extrapyra­ midal symptoms are reversible; however, they may be persistent (see below). The frequency of such reactions DESCRIPTION: is related in part to chemical structure: one can expect a Fluphenazine decanoate is the decanoate ester of a higher incidence with fluphenazine decanoate than with trifluoromethyl phenothiazine derivative. It is a highly less potent piperazine derivatives or with straight­chain potent behavior modifier with a markedly extended dura­ phenothiazines such as chlorpromazine. With any given tion of effect and has the following structural formula: phenothiazine derivative, the incidence and severity of such reactions depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants. (CH2)3 N N CH2 CH2 OCO (CH2)8 CH3 Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These N CF reactions can usually be controlled by administration 3 of antiparkinsonian drugs such as Benztropine Mesy late or Intravenous Caffeine and Sodium Benzoate Injection, and by subsequent reduction in dosage. S Tardive Dyskinesia C H F N O S M.W. 591.8 See WARNINGS. The syndrome is characterized by 32 44 3 3 2 involuntary choreoathetoid movements which variously Fluphenazine Decanoate Injection, USP is available involve the tongue, face, mouth, lips, or jaw (e.g., protru­ as a clear, pale yellow solution for intramuscular (IM) or sion of the tongue, puffing of cheeks, puckering of the subcu ta neous (SC) use providing 25 mg fluphen azine mouth, chewing movements), trunk and extrem ities. The decanoate per mL in a sesame oil vehicle with 12 mg severity of the syndrome and the degree of impairment benzyl alcohol as a preservative. produced vary widely. The syndrome may become clinically recognizable CLINICAL PHARMACOLOGY: either during treatment, upon dosage reduction, or The basic effects of fluphenazine decanoate appear to upon withdrawal of treatment. Early detection of tar­ be no different from those of fluphenazine hydrochlo­ dive dyskinesia is important. To increase the likelihood ride, with the exception of duration of action. The ester­ of detecting the syndrome at the earliest possible time, ification of fluphenazine markedly prolongs the drug’s the dosage of the neuroleptic drug should be reduced duration of effect without unduly attenuating its bene­ periodically (if clinically possible) and the patient ficial action. observed for signs of the disorder. This maneuver is Fluphenazine decanoate has activity at all levels of critical, since neuroleptic drugs may mask the signs of the central nervous system (CNS) as well as on multi ple the syndrome. organ systems. The mechanism whereby its therapeutic action is exerted is unknown. Other CNS Effects Fluphenazine differs from other phenothiazine deriv­ Occurrences of neuroleptic malignant syndrome atives in several respects: it is more potent on a mil­ (NMS) have been reported in patients on neurolep­ ligram basis, it has less potentiating effect on CNS tic therapy (see WARNINGS, Neuroleptic Malignant depressants and anesthetics than do some of the Syndrome); leukocytosis, elevated CPK, liver function phenothiazines and appears to be less sedating, and abnormalities, and acute renal failure may also occur it is less likely than some of the older phenothiazines with NMS. to produce hypotension (nevertheless, appropriate Drowsiness or lethargy, if they occur, may necessitate cautions should be observed, see PRECAUTIONS and a reduction in dosage; the induction of a catatonic­ ADVERSE REACTIONS). like state has been known to occur with dosages of fluphenazine far in excess of the recommended INDICATIONS AND USAGE: amounts. As with other phenothiazine compounds, Fluphenazine Decanoate Injection is a long­acting reactivation or aggravation of psychotic processes may parenteral antipsychotic drug intended for use in the be encountered. management of patients requiring prolonged parenteral Phenothiazine derivatives have been known to cause, neuroleptic therapy (e.g., chronic schizophrenics). in some patients, restlessness, excitement, or bizarre Fluphenazine Decanoate Injection has not been dreams. shown effective in the management of behavioral com­ plications in patients with mental retardation. Autonomic Nervous System Hypertension and fluctuations in blood pressure have CONTRAINDICATIONS: been reported with fluphenazine. Phenothiazines are contraindicated in patients with Hypotension has rarely presented a problem with suspected or established subcortical brain damage. fluphenazine. However, patients with pheochromo­ Phenothiazine compounds should not be used in cytoma, cerebral, vascular or renal insufficiency, or a patients receiving large doses of hypnotics. severe cardiac reserve deficiency such as mitral insuf­ Fluphenazine Decanoate Injection is contraindicated ficiency appear to be particularly prone to hypotensive in comatose or severely depressed states. reactions with phenothiazine compounds, and should The presence of blood dyscrasia or liver damage therefore be observed closely when the drug is admin­ precludes the use of fluphenazine decanoate. istered. If severe hypotension should occur, supportive Fluphenazine Decanoate Injection is not intended for measures including the use of intravenous vaso pressor use in children under 12 years of age. drugs should be instituted immediately. Norepinephrine Fluphenazine Decanoate Injection is contraindicated Bitartrate Injection is the most suitable drug for this in patients who have shown hypersensitivity to fluphen­ purpose: epinephrine should not be used since phe­ azine; cross­sensitivity to phenothiazine deriv atives may nothiazine derivatives have been found to reverse its occur. action, resulting in a further lowering of blood pressure. WARNINGS: Autonomic reactions including nausea and loss of Tardive Dyskinesia appetite, salivation, polyuria, perspiration, dry mouth, Tardive dyskinesia, a syndrome consisting of potentially headache, and constipation may occur. Autonomic irreversible, involuntary, dyskinetic movements, may effects can usually be controlled by reducing or tem­ develop in patients treated with neuroleptic (antipsy­ porarily discontinuing dosage. chotic) drugs. Although the prevalence of the syndrome In some patients, phenothiazine derivatives have appears to be highest among the elderly, especially caused blurred vision, glaucoma, bladder paralysis, elderly women, it is impossible to rely upon prevalence fecal impaction, paralytic ileus, tachycardia, or nasal estimates to predict, at the inception of neuroleptic treat­ congestion. ment, which patients are likely to develop the syndrome. Metabolic and Endocrine Whether neuroleptic drug products differ in their poten­ Weight change, peripheral edema, abnormal lactation, tial to cause tardive dyskinesia is unknown. gynecomastia, menstrual irregularities, false results on Both the risk of developing the syndrome and the pregnancy tests, impotency in men and increased libido likelihood that it will become irreversible are believed in women have all been known to occur in some patients to increase as the duration of treatment and the total on phenothiazine therapy. cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can Allergic Reactions develop, although much less commonly, after relatively Skin disorders such as itching, erythema, urticaria, brief treatment periods at low doses. seb orrhea, photosensitivity, eczema and even exfolia­ There is no known treatment for established cases tive dermatitis have been reported with phenothiazine of tardive dyskinesia, although the syndrome may derivatives. The possibility of anaphylactoid reactions remit, partially or completely, if neuroleptic treatment is occurring in some patients should be borne in mind. withdrawn. Neuroleptic treatment, itself, however, may Hematologic suppress (or partially suppress) the signs and symp­ Routine blood counts are advisable during therapy since toms of the syndrome and thereby may possibly mask blood dyscrasias including leukopenia, agranulocytosis, the underlying disease process. The effect that symp­ thrombocytopenic or nonthrombocytopenic purpura, tomatic suppression has upon the long­term course of eosinophilia, and pancytopenia have been observed the syndrome is unknown. with phenothiazine derivatives. Furthermore, if any sore­ Given these considerations, neuroleptics should ness of the mouth, gums, or throat, or any symptoms be prescribed in a manner that is most likely to mini­ of upper respiratory infection occur and confirmatory mize the occurrence of tardive dyskinesia. Chronic leukocyte count indicates cellular depression, therapy neuroleptic treatment should generally be reserved should be discontinued and other appropriate measures for patients who suffer from a chronic illness that, instituted immediately. 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative equally effective, but potentially less Hepatic harmful treatments are not available or appropriate. In Liver damage as manifested by cholestatic jaundice may patients who do require chronic treatment, the small est be encountered, particularly during the first months of dose and the shortest duration of treatment producing therapy; treatment should be discontinued if this occurs. a satisfactory clinical response should be sought. The An increase in cephalin flocculation, sometimes accom­ need for continued treatment should be reassessed panied by alterations in other liver function tests, has periodically. been reported in patients receiving the enanthate ester If signs and symptoms of tardive dyskinesia appear in of fluphenazine (a closely related compound) who have a patient on neuroleptics, drug discontinuation should had no clinical evidence of liver damage. be considered. However, some patients may require Others treatment despite the presence of the syndrome. Sudden, unexpected and unexplained deaths have (For further information about the description of been reported in hospitalized psychotic patients receiv­ tardive dyskinesia and its clinical detection, please ing phenothiazines. Previous brain damage or seizures refer to the sections on PRECAUTIONS, Information may be predisposing factors; high doses should be for Patients, and ADVERSE REACTIONS, Tardive avoided in known seizure patients. Several patients have Dyskinesia.) shown sudden flare­ups of psychotic behavior patterns Neuroleptic Malignant Syndrome (NMS) shortly before death. Autopsy findings have usually A potentially fatal symptom complex sometimes referred revealed acute fulminating pneumonia or pneumonitis, to as Neuroleptic Malignant Syndrome (NMS) has been aspiration of gastric contents, or intramyocardial lesions. reported in association with antipsychotic drugs. Clinical Although this is not a general feature of fluphenazine, manifestations of NMS are hyperpyrexia, muscle rigidity, potentiation of CNS depressants (opiates, analgesics, altered mental status and evidence of autonomic insta­ antihistamines, barbiturates, alcohol) may occur. bility (irregular pulse or blood pressure, tachycardia, The following adverse reactions have also occurred diaphoresis, and cardiac dysrhythmias). with phenothiazine derivatives: Systemic lupus The diagnostic evaluation of patients with this syn­ erythematosus­like syndrome, hypotension severe drome is complicated. In arriving at a diagnosis, it is enough to cause fatal cardiac arrest, altered electro­ important to identify cases where the clinical presen­ cardiographic and electroencephalographic tracings, tation includes both serious medical illness (e.g., pneu­ altered cerebrospinal fluid proteins, cerebral edema, monia, systemic infection, etc.) and untreated or inad­ asthma, laryngeal edema, and angioneurotic edema; equately treated extrapyramidal signs and symptoms with long­term use, skin pigmentation, and lenticular (EPS). Other important considerations in the differential and corneal opacities. diagnosis include central anticholinergic toxicity, heat Injections of fluphenazine decanoate are extremely stroke, drug fever and primary CNS pathology. well tolerated, local tissue reactions occurring only The management of NMS should include 1) imme­ rarely. diate discontinuation of antipsychotic drugs and other DOSAGE AND ADMINISTRATION: drugs not essential to concurrent therapy, 2) intensive Fluphenazine Decanoate Injection may be given IM symptomatic treatment and medical monitoring, and or SC. A dry syringe and needle of at least 21 gauge 3) treatment of any concomitant serious medical prob­ should be used. Use of a wet needle or syringe may lems for which specific treatments are available. There cause the solution to become cloudy. is no general agreement about specific pharmacological To begin therapy with Fluphenazine Decanoate Injec­ treatment regimens for uncomplicated NMS. tion, the following regimens are suggested: If a patient requires antipsychotic drug treatment after For most patients, a dose of 12.5 to 25 mg (0.5 to recovery from NMS, the potential reintroduction of drug 1 mL) may be given to initiate therapy. The onset of therapy should be carefully considered. The patient action generally appears between 24 and 72 hours after should be carefully monitored, since recurrences of injection and the effects of the drug on psychotic NMS have been reported. symptoms becomes significant within 48 to 96 hours. Others Subsequent injections and the dosage interval are deter­ The use of this drug may impair the mental and phys ical mined in accordance with the patient’s response. When abilities required for driving a car or operating heavy administered as maintenance therapy, a single injection machinery. may be effective in controlling schizophrenic symptoms Physicians should be alert to the possibility that severe up to four weeks or longer. The response to a single adverse reactions may occur which require immediate dose has been found to last as long as six weeks in a medical attention. few patients on maintenance therapy. Potentiation of the effects of alcohol may occur with It may be advisable that patients who have no history the use of this drug. of taking phenothiazines should be treated initially with Since there is no adequate experience in children who a shorter­acting form of fluphenazine before admin­ have received this drug, safety and efficacy in children istering the decanoate to determine the patient’s have not been established. response to fluphenazine and to establish appropri­ ate dosage. For psychotic patients who have been Usage In Pregnancy stabilized on a fixed daily dosage of Fluphenazine The safety for the use of this drug during pregnancy Hydrochloride Tablets, USP or Fluphenazine Hydro­ has not been established; therefore, the possible haz­ chloride Elixir, USP conversion of therapy from these ards should be weighed against the potential benefits short­acting oral forms to the long­acting Fluphenazine when administering this drug to pregnant patients. Decanoate Injection may be indicated. PRECAUTIONS: Appropriate dosage of Fluphenazine Decanoate General Injection should be individualized for each patient and Because of the possibility of cross­sensitivity, flu­ responses carefully monitored. No precise formula can phenazine decanoate should be used cautiously in be given to convert to use of Fluphenazine Decano­ patients who have developed cholestatic jaundice, der­ ate Injection; however, a controlled multicentered matoses, or other allergic reactions to phenothiazine study,* in patients receiving oral doses from 5 to derivatives.

60 mg fluphenazine hydrochloride daily, showed that Psychotic patients on large doses of a phenothiazine m 20 mg fluphenazine hydrochloride daily was equivalent drug who are undergoing surgery should be watched to 25 mg (1 mL) of Fluphenazine Decanoate Injection carefully for possible hypotensive phenomena. More­ every three weeks. This represents an approximate con­

over, it should be remembered that reduced amounts version ratio of 12.5 mg (0.5 mL) of decanoate every of anesthetics or CNS depressants may be necessary. three weeks for every 10 mg of fluphenazine hydro­ The effects of atropine may be potentiated in some chloride daily. patients receiving fluphenazine because of added Once conversion to Fluphenazine Decanoate Injection anticholinergic effects. is made, careful clinical monitoring of the patient and Fluphenazine decanoate should be used cautiously appropriate dosage adjustment should be made at the in patients exposed to extreme heat or phosphorus time of each injection. insecticides. Severely agitated patients may be treated initially with The preparation should be used with caution in a rapid­acting phenothiazine compound such as patients with a history of convulsive disorders, since Fluphenazine Hydrochloride Injection—see Package grand mal convulsions have been known to occur. Insert accompanying that product for complete infor­ Use with caution in patients with special medical dis­ mation. When acute symptoms have subsided, 25 mg orders such as mitral insufficiency or other cardiovas­ (1 mL) of Fluphenazine Decanoate Injection may cular disease and pheo chromocytoma. be administered; subsequent dosage is adjusted as The possibility of liver damage, pigmentary retinopa­ necessary. thy, lenticular and corneal deposits, and development ‘‘Poor risk’’ patients (those with known hypersensi­ of irreversible dyskinesia should be remembered tivity to phenothiazines, or with disorders that predis­ when patients are on prolonged therapy. pose to undue reactions): Therapy may be initiated Outside state hospitals or other psychiatric institu­ cautiously with oral or parenteral fluphenazine hydro­ tions, fluphenazine decanoate should be administered chloride (see Package Inserts accompanying these under the direction of a physician experienced in the products for complete information). When the phar­ clinical use of psychotropic drugs, particularly phe­ macologic effects and an appropriate dosage are nothiazine derivatives. Furthermore, facilities should apparent, an equivalent dose of fluphenazine deca­ be available for periodic checking of hepatic function, noate may be administered. Subsequent dosage ad ­ renal function, and the blood picture. Renal function of just ments are made in accordance with the response patients on long­term therapy should be monitored; if of the patient. blood urea nitrogen (BUN) becomes abnormal, treat­ The optimal amount of the drug and the frequency ment should be discontinued. of administration must be determined for each patient, As with any phenothiazine, the physician should be since dosage requirements have been found to vary alert to the possible development of “silent pneumo­ with clinical circumstances as well as with individual nias” in patients under treatment with fluphenazine response to the drug. decanoate. Dosage should not exceed 100 mg. If doses greater Neuroleptic drugs elevate prolactin levels; the ele­ than 50 mg are deemed necessary, the next dose and vation persists during chronic administration. Tissue succeeding doses should be increased cautiously in culture experiments indicate that approximately one­ increments of 12.5 mg. third of human breast cancers are prolactin dependent Parenteral drug products should be inspected visually in vitro, a factor of potential importance if the prescrip­ for particulate matter and discoloration prior to adminis­ tion of these drugs is contemplated in a patient with a tration, whenever solution and container permit. previously detected breast cancer. Although distur­ HOW SUPPLIED: bances such as galactorrhea, amenorrhea, gyneco­ mastia, and impotence have been reported, the clini­ Product NDC cal significance of elevated serum prolactin levels is No. No. unknown for most patients. An increase in mammary 27205 63323-272-05 Fluphenazine neoplasms has been found in rodents after chronic Decanoate Injection, USP administration of neuroleptic drugs. Neither clinical 25 mg/mL, 5 mL studies nor epidemiologic studies conducted to date, multiple dose, flip- however, have shown an association between chronic top vials individually administration of these drugs and mammary tumorigen­ packaged. esis; the available evidence is considered too limited to Store at 20° to 25°C (68° to 77°F) [see USP Controlled be conclusive at this time. Room Temperature]. Pregnancy PROTECT FROM LIGHT. Non-teratogenic Effects Neonates exposed to antipsychotic drugs, during the Retain vial in carton until ready for use. third trimester of pregnancy are at risk for extrapyramidal Vial stoppers do not contain natural rubber latex. and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, * Schooler, N.R.: The Initiation of Long­Term Pharma­ tremor, somnolence, respiratory distress and feed­ cotherapy in Schizophrenia: Dosage and Side Effect ing disorder in these neonates. These complications Comparisons between Oral and Depot Fluphenazine have varied in severity; while in some cases symptoms Pharmakopsych. 9:159­169, 1976. have been self­limited, in other cases neonates have ” x 24” x ” 4

required intensive care unit support and prolonged ⁄ hospitalization. 1 Fluphenazine Decanoate should be used during preg­ nancy only if the potential benefit justifies the potential risk to the fetus. Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. American Possible risk factors for leukopenia/neutrope­ nia include pre­existing low white blood cell count (WBC) and history of drug induced leukopenia/ APPPharmaceutical Pharmaceuticals, LLC neutropenia. Patients with a pre­existing low WBC Schaumburg, IL 60173 or a history of drug induced leukopenia/neutrope­ Partners, Inc. nia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Fluphenazine 45849F Decanoate Injection, USP at the first sign of a decline Revised: September 2010 in WBC in the absence of other causative factors. Pi Font Typesmiths Helvetica (BT) Mathmatical Pi (A) 9/3/10–bw–indd4 CrossTech–63784–Proof 1 CrossTech–63784–Proof M01 Form 45849F No. 4500071745–Job APP–P.O. Decanoate–2 Fluphenazine Helvetica (A) Fonts: 5Z

Patients with neutropenia should be carefully moni­ tored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. 45849F/Revised: September 2010 Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Fluphenazine Decanoate Injection, USP and have their WBC followed until recovery. FLUPHENAZINE DECANOATE Information for Patients INJECTION, USP Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. ADVERSE REACTIONS: Central Nervous System The side effects most frequently reported with phe­ nothiazine compounds are extrapyramidal symptoms including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyper­ reflexia. Muscle rigidity sometimes accompanied by hyperthermia has been reported following use of fluphenazine decanoate. Most often these extrapyra­ midal symptoms are reversible; however, they may be persistent (see below). The frequency of such reactions DESCRIPTION: is related in part to chemical structure: one can expect a Fluphenazine decanoate is the decanoate ester of a higher incidence with fluphenazine decanoate than with trifluoromethyl phenothiazine derivative. It is a highly less potent piperazine derivatives or with straight­chain potent behavior modifier with a markedly extended dura­ phenothiazines such as chlorpromazine. With any given tion of effect and has the following structural formula: phenothiazine derivative, the incidence and severity of such reactions depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants. (CH2)3 N N CH2 CH2 OCO (CH2)8 CH3 Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These N CF reactions can usually be controlled by administration 3 of antiparkinsonian drugs such as Benztropine Mesy late or Intravenous Caffeine and Sodium Benzoate Injection, and by subsequent reduction in dosage. S Tardive Dyskinesia C H F N O S M.W. 591.8 See WARNINGS. The syndrome is characterized by 32 44 3 3 2 involuntary choreoathetoid movements which variously Fluphenazine Decanoate Injection, USP is available involve the tongue, face, mouth, lips, or jaw (e.g., protru­ as a clear, pale yellow solution for intramuscular (IM) or sion of the tongue, puffing of cheeks, puckering of the subcu ta neous (SC) use providing 25 mg fluphen azine mouth, chewing movements), trunk and extrem ities. The decanoate per mL in a sesame oil vehicle with 12 mg severity of the syndrome and the degree of impairment benzyl alcohol as a preservative. produced vary widely. The syndrome may become clinically recognizable CLINICAL PHARMACOLOGY: either during treatment, upon dosage reduction, or The basic effects of fluphenazine decanoate appear to upon withdrawal of treatment. Early detection of tar­ be no different from those of fluphenazine hydrochlo­ dive dyskinesia is important. To increase the likelihood ride, with the exception of duration of action. The ester­ of detecting the syndrome at the earliest possible time, ification of fluphenazine markedly prolongs the drug’s the dosage of the neuroleptic drug should be reduced duration of effect without unduly attenuating its bene­ periodically (if clinically possible) and the patient ficial action. observed for signs of the disorder. This maneuver is Fluphenazine decanoate has activity at all levels of critical, since neuroleptic drugs may mask the signs of the central nervous system (CNS) as well as on multi ple the syndrome. organ systems. The mechanism whereby its therapeutic action is exerted is unknown. Other CNS Effects Fluphenazine differs from other phenothiazine deriv­ Occurrences of neuroleptic malignant syndrome atives in several respects: it is more potent on a mil­ (NMS) have been reported in patients on neurolep­ ligram basis, it has less potentiating effect on CNS tic therapy (see WARNINGS, Neuroleptic Malignant depressants and anesthetics than do some of the Syndrome); leukocytosis, elevated CPK, liver function phenothiazines and appears to be less sedating, and abnormalities, and acute renal failure may also occur it is less likely than some of the older phenothiazines with NMS. to produce hypotension (nevertheless, appropriate Drowsiness or lethargy, if they occur, may necessitate cautions should be observed, see PRECAUTIONS and a reduction in dosage; the induction of a catatonic­ ADVERSE REACTIONS). like state has been known to occur with dosages of fluphenazine far in excess of the recommended INDICATIONS AND USAGE: amounts. As with other phenothiazine compounds, Fluphenazine Decanoate Injection is a long­acting reactivation or aggravation of psychotic processes may parenteral antipsychotic drug intended for use in the be encountered. management of patients requiring prolonged parenteral Phenothiazine derivatives have been known to cause, neuroleptic therapy (e.g., chronic schizophrenics). in some patients, restlessness, excitement, or bizarre Fluphenazine Decanoate Injection has not been dreams. shown effective in the management of behavioral com­ plications in patients with mental retardation. Autonomic Nervous System Hypertension and fluctuations in blood pressure have CONTRAINDICATIONS: been reported with fluphenazine. Phenothiazines are contraindicated in patients with Hypotension has rarely presented a problem with suspected or established subcortical brain damage. fluphenazine. However, patients with pheochromo­ Phenothiazine compounds should not be used in cytoma, cerebral, vascular or renal insufficiency, or a patients receiving large doses of hypnotics. severe cardiac reserve deficiency such as mitral insuf­ Fluphenazine Decanoate Injection is contraindicated ficiency appear to be particularly prone to hypotensive in comatose or severely depressed states. reactions with phenothiazine compounds, and should The presence of blood dyscrasia or liver damage therefore be observed closely when the drug is admin­ precludes the use of fluphenazine decanoate. istered. If severe hypotension should occur, supportive Fluphenazine Decanoate Injection is not intended for measures including the use of intravenous vaso pressor use in children under 12 years of age. drugs should be instituted immediately. Norepinephrine Fluphenazine Decanoate Injection is contraindicated Bitartrate Injection is the most suitable drug for this in patients who have shown hypersensitivity to fluphen­ purpose: epinephrine should not be used since phe­ azine; cross­sensitivity to phenothiazine deriv atives may nothiazine derivatives have been found to reverse its occur. action, resulting in a further lowering of blood pressure. WARNINGS: Autonomic reactions including nausea and loss of Tardive Dyskinesia appetite, salivation, polyuria, perspiration, dry mouth, Tardive dyskinesia, a syndrome consisting of potentially headache, and constipation may occur. Autonomic irreversible, involuntary, dyskinetic movements, may effects can usually be controlled by reducing or tem­ develop in patients treated with neuroleptic (antipsy­ porarily discontinuing dosage. chotic) drugs. Although the prevalence of the syndrome In some patients, phenothiazine derivatives have appears to be highest among the elderly, especially caused blurred vision, glaucoma, bladder paralysis, elderly women, it is impossible to rely upon prevalence fecal impaction, paralytic ileus, tachycardia, or nasal estimates to predict, at the inception of neuroleptic treat­ congestion. ment, which patients are likely to develop the syndrome. Metabolic and Endocrine Whether neuroleptic drug products differ in their poten­ Weight change, peripheral edema, abnormal lactation, tial to cause tardive dyskinesia is unknown. gynecomastia, menstrual irregularities, false results on Both the risk of developing the syndrome and the pregnancy tests, impotency in men and increased libido likelihood that it will become irreversible are believed in women have all been known to occur in some patients to increase as the duration of treatment and the total on phenothiazine therapy. cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can Allergic Reactions develop, although much less commonly, after relatively Skin disorders such as itching, erythema, urticaria, brief treatment periods at low doses. seb orrhea, photosensitivity, eczema and even exfolia­ There is no known treatment for established cases tive dermatitis have been reported with phenothiazine of tardive dyskinesia, although the syndrome may derivatives. The possibility of anaphylactoid reactions remit, partially or completely, if neuroleptic treatment is occurring in some patients should be borne in mind. withdrawn. Neuroleptic treatment, itself, however, may Hematologic suppress (or partially suppress) the signs and symp­ Routine blood counts are advisable during therapy since toms of the syndrome and thereby may possibly mask blood dyscrasias including leukopenia, agranulocytosis, the underlying disease process. The effect that symp­ thrombocytopenic or nonthrombocytopenic purpura, tomatic suppression has upon the long­term course of eosinophilia, and pancytopenia have been observed the syndrome is unknown. with phenothiazine derivatives. Furthermore, if any sore­ Given these considerations, neuroleptics should ness of the mouth, gums, or throat, or any symptoms be prescribed in a manner that is most likely to mini­ of upper respiratory infection occur and confirmatory mize the occurrence of tardive dyskinesia. Chronic leukocyte count indicates cellular depression, therapy neuroleptic treatment should generally be reserved should be discontinued and other appropriate measures for patients who suffer from a chronic illness that, instituted immediately. 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative equally effective, but potentially less Hepatic harmful treatments are not available or appropriate. In Liver damage as manifested by cholestatic jaundice may patients who do require chronic treatment, the small est be encountered, particularly during the first months of dose and the shortest duration of treatment producing therapy; treatment should be discontinued if this occurs. a satisfactory clinical response should be sought. The An increase in cephalin flocculation, sometimes accom­ need for continued treatment should be reassessed panied by alterations in other liver function tests, has periodically. been reported in patients receiving the enanthate ester If signs and symptoms of tardive dyskinesia appear in of fluphenazine (a closely related compound) who have a patient on neuroleptics, drug discontinuation should had no clinical evidence of liver damage. be considered. However, some patients may require Others treatment despite the presence of the syndrome. Sudden, unexpected and unexplained deaths have (For further information about the description of been reported in hospitalized psychotic patients receiv­ tardive dyskinesia and its clinical detection, please ing phenothiazines. Previous brain damage or seizures refer to the sections on PRECAUTIONS, Information may be predisposing factors; high doses should be for Patients, and ADVERSE REACTIONS, Tardive avoided in known seizure patients. Several patients have Dyskinesia.) shown sudden flare­ups of psychotic behavior patterns Neuroleptic Malignant Syndrome (NMS) shortly before death. Autopsy findings have usually A potentially fatal symptom complex sometimes referred revealed acute fulminating pneumonia or pneumonitis, to as Neuroleptic Malignant Syndrome (NMS) has been aspiration of gastric contents, or intramyocardial lesions. reported in association with antipsychotic drugs. Clinical Although this is not a general feature of fluphenazine, manifestations of NMS are hyperpyrexia, muscle rigidity, potentiation of CNS depressants (opiates, analgesics, altered mental status and evidence of autonomic insta­ antihistamines, barbiturates, alcohol) may occur. bility (irregular pulse or blood pressure, tachycardia, The following adverse reactions have also occurred diaphoresis, and cardiac dysrhythmias). with phenothiazine derivatives: Systemic lupus The diagnostic evaluation of patients with this syn­ erythematosus­like syndrome, hypotension severe drome is complicated. In arriving at a diagnosis, it is enough to cause fatal cardiac arrest, altered electro­ important to identify cases where the clinical presen­ cardiographic and electroencephalographic tracings, tation includes both serious medical illness (e.g., pneu­ altered cerebrospinal fluid proteins, cerebral edema, monia, systemic infection, etc.) and untreated or inad­ asthma, laryngeal edema, and angioneurotic edema; equately treated extrapyramidal signs and symptoms with long­term use, skin pigmentation, and lenticular (EPS). Other important considerations in the differential and corneal opacities. diagnosis include central anticholinergic toxicity, heat Injections of fluphenazine decanoate are extremely stroke, drug fever and primary CNS pathology. well tolerated, local tissue reactions occurring only The management of NMS should include 1) imme­ rarely. diate discontinuation of antipsychotic drugs and other DOSAGE AND ADMINISTRATION: drugs not essential to concurrent therapy, 2) intensive Fluphenazine Decanoate Injection may be given IM symptomatic treatment and medical monitoring, and or SC. A dry syringe and needle of at least 21 gauge 3) treatment of any concomitant serious medical prob­ should be used. Use of a wet needle or syringe may lems for which specific treatments are available. There cause the solution to become cloudy. is no general agreement about specific pharmacological To begin therapy with Fluphenazine Decanoate Injec­ treatment regimens for uncomplicated NMS. tion, the following regimens are suggested: If a patient requires antipsychotic drug treatment after For most patients, a dose of 12.5 to 25 mg (0.5 to recovery from NMS, the potential reintroduction of drug 1 mL) may be given to initiate therapy. The onset of therapy should be carefully considered. The patient action generally appears between 24 and 72 hours after should be carefully monitored, since recurrences of injection and the effects of the drug on psychotic NMS have been reported. symptoms becomes significant within 48 to 96 hours. Others Subsequent injections and the dosage interval are deter­ The use of this drug may impair the mental and phys ical mined in accordance with the patient’s response. When abilities required for driving a car or operating heavy administered as maintenance therapy, a single injection machinery. may be effective in controlling schizophrenic symptoms Physicians should be alert to the possibility that severe up to four weeks or longer. The response to a single adverse reactions may occur which require immediate dose has been found to last as long as six weeks in a medical attention. few patients on maintenance therapy. Potentiation of the effects of alcohol may occur with It may be advisable that patients who have no history the use of this drug. of taking phenothiazines should be treated initially with Since there is no adequate experience in children who a shorter­acting form of fluphenazine before admin­ have received this drug, safety and efficacy in children istering the decanoate to determine the patient’s have not been established. response to fluphenazine and to establish appropri­ ate dosage. For psychotic patients who have been Usage In Pregnancy stabilized on a fixed daily dosage of Fluphenazine The safety for the use of this drug during pregnancy Hydrochloride Tablets, USP or Fluphenazine Hydro­ has not been established; therefore, the possible haz­ chloride Elixir, USP conversion of therapy from these ards should be weighed against the potential benefits short­acting oral forms to the long­acting Fluphenazine when administering this drug to pregnant patients. Decanoate Injection may be indicated. PRECAUTIONS: Appropriate dosage of Fluphenazine Decanoate General Injection should be individualized for each patient and Because of the possibility of cross­sensitivity, flu­ responses carefully monitored. No precise formula can phenazine decanoate should be used cautiously in be given to convert to use of Fluphenazine Decano­ patients who have developed cholestatic jaundice, der­ ate Injection; however, a controlled multicentered matoses, or other allergic reactions to phenothiazine study,* in patients receiving oral doses from 5 to derivatives.

60 mg fluphenazine hydrochloride daily, showed that Psychotic patients on large doses of a phenothiazine m 20 mg fluphenazine hydrochloride daily was equivalent drug who are undergoing surgery should be watched to 25 mg (1 mL) of Fluphenazine Decanoate Injection carefully for possible hypotensive phenomena. More­ every three weeks. This represents an approximate con­

over, it should be remembered that reduced amounts version ratio of 12.5 mg (0.5 mL) of decanoate every of anesthetics or CNS depressants may be necessary. three weeks for every 10 mg of fluphenazine hydro­ The effects of atropine may be potentiated in some chloride daily. patients receiving fluphenazine because of added Once conversion to Fluphenazine Decanoate Injection anticholinergic effects. is made, careful clinical monitoring of the patient and Fluphenazine decanoate should be used cautiously appropriate dosage adjustment should be made at the in patients exposed to extreme heat or phosphorus time of each injection. insecticides. Severely agitated patients may be treated initially with The preparation should be used with caution in a rapid­acting phenothiazine compound such as patients with a history of convulsive disorders, since Fluphenazine Hydrochloride Injection—see Package grand mal convulsions have been known to occur. Insert accompanying that product for complete infor­ Use with caution in patients with special medical dis­ mation. When acute symptoms have subsided, 25 mg orders such as mitral insufficiency or other cardiovas­ (1 mL) of Fluphenazine Decanoate Injection may cular disease and pheo chromocytoma. be administered; subsequent dosage is adjusted as The possibility of liver damage, pigmentary retinopa­ necessary. thy, lenticular and corneal deposits, and development ‘‘Poor risk’’ patients (those with known hypersensi­ of irreversible dyskinesia should be remembered tivity to phenothiazines, or with disorders that predis­ when patients are on prolonged therapy. pose to undue reactions): Therapy may be initiated Outside state hospitals or other psychiatric institu­ cautiously with oral or parenteral fluphenazine hydro­ tions, fluphenazine decanoate should be administered chloride (see Package Inserts accompanying these under the direction of a physician experienced in the products for complete information). When the phar­ clinical use of psychotropic drugs, particularly phe­ macologic effects and an appropriate dosage are nothiazine derivatives. Furthermore, facilities should apparent, an equivalent dose of fluphenazine deca­ be available for periodic checking of hepatic function, noate may be administered. Subsequent dosage ad ­ renal function, and the blood picture. Renal function of just ments are made in accordance with the response patients on long­term therapy should be monitored; if of the patient. blood urea nitrogen (BUN) becomes abnormal, treat­ The optimal amount of the drug and the frequency ment should be discontinued. of administration must be determined for each patient, As with any phenothiazine, the physician should be since dosage requirements have been found to vary alert to the possible development of “silent pneumo­ with clinical circumstances as well as with individual nias” in patients under treatment with fluphenazine response to the drug. decanoate. Dosage should not exceed 100 mg. If doses greater Neuroleptic drugs elevate prolactin levels; the ele­ than 50 mg are deemed necessary, the next dose and vation persists during chronic administration. Tissue succeeding doses should be increased cautiously in culture experiments indicate that approximately one­ increments of 12.5 mg. third of human breast cancers are prolactin dependent Parenteral drug products should be inspected visually in vitro, a factor of potential importance if the prescrip­ for particulate matter and discoloration prior to adminis­ tion of these drugs is contemplated in a patient with a tration, whenever solution and container permit. previously detected breast cancer. Although distur­ HOW SUPPLIED: bances such as galactorrhea, amenorrhea, gyneco­ mastia, and impotence have been reported, the clini­ Product NDC cal significance of elevated serum prolactin levels is No. No. unknown for most patients. An increase in mammary 27205 63323-272-05 Fluphenazine neoplasms has been found in rodents after chronic Decanoate Injection, USP administration of neuroleptic drugs. Neither clinical 25 mg/mL, 5 mL studies nor epidemiologic studies conducted to date, multiple dose, flip- however, have shown an association between chronic top vials individually administration of these drugs and mammary tumorigen­ packaged. esis; the available evidence is considered too limited to Store at 20° to 25°C (68° to 77°F) [see USP Controlled be conclusive at this time. Room Temperature]. Pregnancy PROTECT FROM LIGHT. Non-teratogenic Effects Neonates exposed to antipsychotic drugs, during the Retain vial in carton until ready for use. third trimester of pregnancy are at risk for extrapyramidal Vial stoppers do not contain natural rubber latex. and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, * Schooler, N.R.: The Initiation of Long­Term Pharma­ tremor, somnolence, respiratory distress and feed­ cotherapy in Schizophrenia: Dosage and Side Effect ing disorder in these neonates. These complications Comparisons between Oral and Depot Fluphenazine have varied in severity; while in some cases symptoms Pharmakopsych. 9:159­169, 1976. have been self­limited, in other cases neonates have ” x 24” x ” 4

required intensive care unit support and prolonged ⁄ hospitalization. 1 Fluphenazine Decanoate should be used during preg­ nancy only if the potential benefit justifies the potential risk to the fetus. Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. American Possible risk factors for leukopenia/neutrope­ nia include pre­existing low white blood cell count (WBC) and history of drug induced leukopenia/ APPPharmaceutical Pharmaceuticals, LLC neutropenia. Patients with a pre­existing low WBC Schaumburg, IL 60173 or a history of drug induced leukopenia/neutrope­ Partners, Inc. nia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Fluphenazine 45849F Decanoate Injection, USP at the first sign of a decline Revised: September 2010 in WBC in the absence of other causative factors. Pi Font Typesmiths Helvetica (BT) Mathmatical Pi (A) 9/3/10–bw–indd4 CrossTech–63784–Proof 1 CrossTech–63784–Proof M01 Form 45849F No. 4500071745–Job APP–P.O. Decanoate–2 Fluphenazine Helvetica (A) Fonts: 5Z

Patients with neutropenia should be carefully moni­ tored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. 45849F/Revised: September 2010 Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Fluphenazine Decanoate Injection, USP and have their WBC followed until recovery. FLUPHENAZINE DECANOATE Information for Patients INJECTION, USP Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. ADVERSE REACTIONS: Central Nervous System The side effects most frequently reported with phe­ nothiazine compounds are extrapyramidal symptoms including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyper­ reflexia. Muscle rigidity sometimes accompanied by hyperthermia has been reported following use of fluphenazine decanoate. Most often these extrapyra­ midal symptoms are reversible; however, they may be persistent (see below). The frequency of such reactions DESCRIPTION: is related in part to chemical structure: one can expect a Fluphenazine decanoate is the decanoate ester of a higher incidence with fluphenazine decanoate than with trifluoromethyl phenothiazine derivative. It is a highly less potent piperazine derivatives or with straight­chain potent behavior modifier with a markedly extended dura­ phenothiazines such as chlorpromazine. With any given tion of effect and has the following structural formula: phenothiazine derivative, the incidence and severity of such reactions depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants. (CH2)3 N N CH2 CH2 OCO (CH2)8 CH3 Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These N CF reactions can usually be controlled by administration 3 of antiparkinsonian drugs such as Benztropine Mesy late or Intravenous Caffeine and Sodium Benzoate Injection, and by subsequent reduction in dosage. S Tardive Dyskinesia C H F N O S M.W. 591.8 See WARNINGS. The syndrome is characterized by 32 44 3 3 2 involuntary choreoathetoid movements which variously Fluphenazine Decanoate Injection, USP is available involve the tongue, face, mouth, lips, or jaw (e.g., protru­ as a clear, pale yellow solution for intramuscular (IM) or sion of the tongue, puffing of cheeks, puckering of the subcu ta neous (SC) use providing 25 mg fluphen azine mouth, chewing movements), trunk and extrem ities. The decanoate per mL in a sesame oil vehicle with 12 mg severity of the syndrome and the degree of impairment benzyl alcohol as a preservative. produced vary widely. The syndrome may become clinically recognizable CLINICAL PHARMACOLOGY: either during treatment, upon dosage reduction, or The basic effects of fluphenazine decanoate appear to upon withdrawal of treatment. Early detection of tar­ be no different from those of fluphenazine hydrochlo­ dive dyskinesia is important. To increase the likelihood ride, with the exception of duration of action. The ester­ of detecting the syndrome at the earliest possible time, ification of fluphenazine markedly prolongs the drug’s the dosage of the neuroleptic drug should be reduced duration of effect without unduly attenuating its bene­ periodically (if clinically possible) and the patient ficial action. observed for signs of the disorder. This maneuver is Fluphenazine decanoate has activity at all levels of critical, since neuroleptic drugs may mask the signs of the central nervous system (CNS) as well as on multi ple the syndrome. organ systems. The mechanism whereby its therapeutic action is exerted is unknown. Other CNS Effects Fluphenazine differs from other phenothiazine deriv­ Occurrences of neuroleptic malignant syndrome atives in several respects: it is more potent on a mil­ (NMS) have been reported in patients on neurolep­ ligram basis, it has less potentiating effect on CNS tic therapy (see WARNINGS, Neuroleptic Malignant depressants and anesthetics than do some of the Syndrome); leukocytosis, elevated CPK, liver function phenothiazines and appears to be less sedating, and abnormalities, and acute renal failure may also occur it is less likely than some of the older phenothiazines with NMS. to produce hypotension (nevertheless, appropriate Drowsiness or lethargy, if they occur, may necessitate cautions should be observed, see PRECAUTIONS and a reduction in dosage; the induction of a catatonic­ ADVERSE REACTIONS). like state has been known to occur with dosages of fluphenazine far in excess of the recommended INDICATIONS AND USAGE: amounts. As with other phenothiazine compounds, Fluphenazine Decanoate Injection is a long­acting reactivation or aggravation of psychotic processes may parenteral antipsychotic drug intended for use in the be encountered. management of patients requiring prolonged parenteral Phenothiazine derivatives have been known to cause, neuroleptic therapy (e.g., chronic schizophrenics). in some patients, restlessness, excitement, or bizarre Fluphenazine Decanoate Injection has not been dreams. shown effective in the management of behavioral com­ plications in patients with mental retardation. Autonomic Nervous System Hypertension and fluctuations in blood pressure have CONTRAINDICATIONS: been reported with fluphenazine. Phenothiazines are contraindicated in patients with Hypotension has rarely presented a problem with suspected or established subcortical brain damage. fluphenazine. However, patients with pheochromo­ Phenothiazine compounds should not be used in cytoma, cerebral, vascular or renal insufficiency, or a patients receiving large doses of hypnotics. severe cardiac reserve deficiency such as mitral insuf­ Fluphenazine Decanoate Injection is contraindicated ficiency appear to be particularly prone to hypotensive in comatose or severely depressed states. reactions with phenothiazine compounds, and should The presence of blood dyscrasia or liver damage therefore be observed closely when the drug is admin­ precludes the use of fluphenazine decanoate. istered. If severe hypotension should occur, supportive Fluphenazine Decanoate Injection is not intended for measures including the use of intravenous vaso pressor use in children under 12 years of age. drugs should be instituted immediately. Norepinephrine Fluphenazine Decanoate Injection is contraindicated Bitartrate Injection is the most suitable drug for this in patients who have shown hypersensitivity to fluphen­ purpose: epinephrine should not be used since phe­ azine; cross­sensitivity to phenothiazine deriv atives may nothiazine derivatives have been found to reverse its occur. action, resulting in a further lowering of blood pressure. WARNINGS: Autonomic reactions including nausea and loss of Tardive Dyskinesia appetite, salivation, polyuria, perspiration, dry mouth, Tardive dyskinesia, a syndrome consisting of potentially headache, and constipation may occur. Autonomic irreversible, involuntary, dyskinetic movements, may effects can usually be controlled by reducing or tem­ develop in patients treated with neuroleptic (antipsy­ porarily discontinuing dosage. chotic) drugs. Although the prevalence of the syndrome In some patients, phenothiazine derivatives have appears to be highest among the elderly, especially caused blurred vision, glaucoma, bladder paralysis, elderly women, it is impossible to rely upon prevalence fecal impaction, paralytic ileus, tachycardia, or nasal estimates to predict, at the inception of neuroleptic treat­ congestion. ment, which patients are likely to develop the syndrome. Metabolic and Endocrine Whether neuroleptic drug products differ in their poten­ Weight change, peripheral edema, abnormal lactation, tial to cause tardive dyskinesia is unknown. gynecomastia, menstrual irregularities, false results on Both the risk of developing the syndrome and the pregnancy tests, impotency in men and increased libido likelihood that it will become irreversible are believed in women have all been known to occur in some patients to increase as the duration of treatment and the total on phenothiazine therapy. cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can Allergic Reactions develop, although much less commonly, after relatively Skin disorders such as itching, erythema, urticaria, brief treatment periods at low doses. seb orrhea, photosensitivity, eczema and even exfolia­ There is no known treatment for established cases tive dermatitis have been reported with phenothiazine of tardive dyskinesia, although the syndrome may derivatives. The possibility of anaphylactoid reactions remit, partially or completely, if neuroleptic treatment is occurring in some patients should be borne in mind. withdrawn. Neuroleptic treatment, itself, however, may Hematologic suppress (or partially suppress) the signs and symp­ Routine blood counts are advisable during therapy since toms of the syndrome and thereby may possibly mask blood dyscrasias including leukopenia, agranulocytosis, the underlying disease process. The effect that symp­ thrombocytopenic or nonthrombocytopenic purpura, tomatic suppression has upon the long­term course of eosinophilia, and pancytopenia have been observed the syndrome is unknown. with phenothiazine derivatives. Furthermore, if any sore­ Given these considerations, neuroleptics should ness of the mouth, gums, or throat, or any symptoms be prescribed in a manner that is most likely to mini­ of upper respiratory infection occur and confirmatory mize the occurrence of tardive dyskinesia. Chronic leukocyte count indicates cellular depression, therapy neuroleptic treatment should generally be reserved should be discontinued and other appropriate measures for patients who suffer from a chronic illness that, instituted immediately. 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative equally effective, but potentially less Hepatic harmful treatments are not available or appropriate. In Liver damage as manifested by cholestatic jaundice may patients who do require chronic treatment, the small est be encountered, particularly during the first months of dose and the shortest duration of treatment producing therapy; treatment should be discontinued if this occurs. a satisfactory clinical response should be sought. The An increase in cephalin flocculation, sometimes accom­ need for continued treatment should be reassessed panied by alterations in other liver function tests, has periodically. been reported in patients receiving the enanthate ester If signs and symptoms of tardive dyskinesia appear in of fluphenazine (a closely related compound) who have a patient on neuroleptics, drug discontinuation should had no clinical evidence of liver damage. be considered. However, some patients may require Others treatment despite the presence of the syndrome. Sudden, unexpected and unexplained deaths have (For further information about the description of been reported in hospitalized psychotic patients receiv­ tardive dyskinesia and its clinical detection, please ing phenothiazines. Previous brain damage or seizures refer to the sections on PRECAUTIONS, Information may be predisposing factors; high doses should be for Patients, and ADVERSE REACTIONS, Tardive avoided in known seizure patients. Several patients have Dyskinesia.) shown sudden flare­ups of psychotic behavior patterns Neuroleptic Malignant Syndrome (NMS) shortly before death. Autopsy findings have usually A potentially fatal symptom complex sometimes referred revealed acute fulminating pneumonia or pneumonitis, to as Neuroleptic Malignant Syndrome (NMS) has been aspiration of gastric contents, or intramyocardial lesions. reported in association with antipsychotic drugs. Clinical Although this is not a general feature of fluphenazine, manifestations of NMS are hyperpyrexia, muscle rigidity, potentiation of CNS depressants (opiates, analgesics, altered mental status and evidence of autonomic insta­ antihistamines, barbiturates, alcohol) may occur. bility (irregular pulse or blood pressure, tachycardia, The following adverse reactions have also occurred diaphoresis, and cardiac dysrhythmias). with phenothiazine derivatives: Systemic lupus The diagnostic evaluation of patients with this syn­ erythematosus­like syndrome, hypotension severe drome is complicated. In arriving at a diagnosis, it is enough to cause fatal cardiac arrest, altered electro­ important to identify cases where the clinical presen­ cardiographic and electroencephalographic tracings, tation includes both serious medical illness (e.g., pneu­ altered cerebrospinal fluid proteins, cerebral edema, monia, systemic infection, etc.) and untreated or inad­ asthma, laryngeal edema, and angioneurotic edema; equately treated extrapyramidal signs and symptoms with long­term use, skin pigmentation, and lenticular (EPS). Other important considerations in the differential and corneal opacities. diagnosis include central anticholinergic toxicity, heat Injections of fluphenazine decanoate are extremely stroke, drug fever and primary CNS pathology. well tolerated, local tissue reactions occurring only The management of NMS should include 1) imme­ rarely. diate discontinuation of antipsychotic drugs and other DOSAGE AND ADMINISTRATION: drugs not essential to concurrent therapy, 2) intensive Fluphenazine Decanoate Injection may be given IM symptomatic treatment and medical monitoring, and or SC. A dry syringe and needle of at least 21 gauge 3) treatment of any concomitant serious medical prob­ should be used. Use of a wet needle or syringe may lems for which specific treatments are available. There cause the solution to become cloudy. is no general agreement about specific pharmacological To begin therapy with Fluphenazine Decanoate Injec­ treatment regimens for uncomplicated NMS. tion, the following regimens are suggested: If a patient requires antipsychotic drug treatment after For most patients, a dose of 12.5 to 25 mg (0.5 to recovery from NMS, the potential reintroduction of drug 1 mL) may be given to initiate therapy. The onset of therapy should be carefully considered. The patient action generally appears between 24 and 72 hours after should be carefully monitored, since recurrences of injection and the effects of the drug on psychotic NMS have been reported. symptoms becomes significant within 48 to 96 hours. Others Subsequent injections and the dosage interval are deter­ The use of this drug may impair the mental and phys ical mined in accordance with the patient’s response. When abilities required for driving a car or operating heavy administered as maintenance therapy, a single injection machinery. may be effective in controlling schizophrenic symptoms Physicians should be alert to the possibility that severe up to four weeks or longer. The response to a single adverse reactions may occur which require immediate dose has been found to last as long as six weeks in a medical attention. few patients on maintenance therapy. Potentiation of the effects of alcohol may occur with It may be advisable that patients who have no history the use of this drug. of taking phenothiazines should be treated initially with Since there is no adequate experience in children who a shorter­acting form of fluphenazine before admin­ have received this drug, safety and efficacy in children istering the decanoate to determine the patient’s have not been established. response to fluphenazine and to establish appropri­ ate dosage. For psychotic patients who have been Usage In Pregnancy stabilized on a fixed daily dosage of Fluphenazine The safety for the use of this drug during pregnancy Hydrochloride Tablets, USP or Fluphenazine Hydro­ has not been established; therefore, the possible haz­ chloride Elixir, USP conversion of therapy from these ards should be weighed against the potential benefits short­acting oral forms to the long­acting Fluphenazine when administering this drug to pregnant patients. Decanoate Injection may be indicated. PRECAUTIONS: Appropriate dosage of Fluphenazine Decanoate General Injection should be individualized for each patient and Because of the possibility of cross­sensitivity, flu­ responses carefully monitored. No precise formula can phenazine decanoate should be used cautiously in be given to convert to use of Fluphenazine Decano­ patients who have developed cholestatic jaundice, der­ ate Injection; however, a controlled multicentered matoses, or other allergic reactions to phenothiazine study,* in patients receiving oral doses from 5 to derivatives.

60 mg fluphenazine hydrochloride daily, showed that Psychotic patients on large doses of a phenothiazine m 20 mg fluphenazine hydrochloride daily was equivalent drug who are undergoing surgery should be watched to 25 mg (1 mL) of Fluphenazine Decanoate Injection carefully for possible hypotensive phenomena. More­ every three weeks. This represents an approximate con­

over, it should be remembered that reduced amounts version ratio of 12.5 mg (0.5 mL) of decanoate every of anesthetics or CNS depressants may be necessary. three weeks for every 10 mg of fluphenazine hydro­ The effects of atropine may be potentiated in some chloride daily. patients receiving fluphenazine because of added Once conversion to Fluphenazine Decanoate Injection anticholinergic effects. is made, careful clinical monitoring of the patient and Fluphenazine decanoate should be used cautiously appropriate dosage adjustment should be made at the in patients exposed to extreme heat or phosphorus time of each injection. insecticides. Severely agitated patients may be treated initially with The preparation should be used with caution in a rapid­acting phenothiazine compound such as patients with a history of convulsive disorders, since Fluphenazine Hydrochloride Injection—see Package grand mal convulsions have been known to occur. Insert accompanying that product for complete infor­ Use with caution in patients with special medical dis­ mation. When acute symptoms have subsided, 25 mg orders such as mitral insufficiency or other cardiovas­ (1 mL) of Fluphenazine Decanoate Injection may cular disease and pheo chromocytoma. be administered; subsequent dosage is adjusted as The possibility of liver damage, pigmentary retinopa­ necessary. thy, lenticular and corneal deposits, and development ‘‘Poor risk’’ patients (those with known hypersensi­ of irreversible dyskinesia should be remembered tivity to phenothiazines, or with disorders that predis­ when patients are on prolonged therapy. pose to undue reactions): Therapy may be initiated Outside state hospitals or other psychiatric institu­ cautiously with oral or parenteral fluphenazine hydro­ tions, fluphenazine decanoate should be administered chloride (see Package Inserts accompanying these under the direction of a physician experienced in the products for complete information). When the phar­ clinical use of psychotropic drugs, particularly phe­ macologic effects and an appropriate dosage are nothiazine derivatives. Furthermore, facilities should apparent, an equivalent dose of fluphenazine deca­ be available for periodic checking of hepatic function, noate may be administered. Subsequent dosage ad ­ renal function, and the blood picture. Renal function of just ments are made in accordance with the response patients on long­term therapy should be monitored; if of the patient. blood urea nitrogen (BUN) becomes abnormal, treat­ The optimal amount of the drug and the frequency ment should be discontinued. of administration must be determined for each patient, As with any phenothiazine, the physician should be since dosage requirements have been found to vary alert to the possible development of “silent pneumo­ with clinical circumstances as well as with individual nias” in patients under treatment with fluphenazine response to the drug. decanoate. Dosage should not exceed 100 mg. If doses greater Neuroleptic drugs elevate prolactin levels; the ele­ than 50 mg are deemed necessary, the next dose and vation persists during chronic administration. Tissue succeeding doses should be increased cautiously in culture experiments indicate that approximately one­ increments of 12.5 mg. third of human breast cancers are prolactin dependent Parenteral drug products should be inspected visually in vitro, a factor of potential importance if the prescrip­ for particulate matter and discoloration prior to adminis­ tion of these drugs is contemplated in a patient with a tration, whenever solution and container permit. previously detected breast cancer. Although distur­ HOW SUPPLIED: bances such as galactorrhea, amenorrhea, gyneco­ mastia, and impotence have been reported, the clini­ Product NDC cal significance of elevated serum prolactin levels is No. No. unknown for most patients. An increase in mammary 27205 63323-272-05 Fluphenazine neoplasms has been found in rodents after chronic Decanoate Injection, USP administration of neuroleptic drugs. Neither clinical 25 mg/mL, 5 mL studies nor epidemiologic studies conducted to date, multiple dose, flip- however, have shown an association between chronic top vials individually administration of these drugs and mammary tumorigen­ packaged. esis; the available evidence is considered too limited to Store at 20° to 25°C (68° to 77°F) [see USP Controlled be conclusive at this time. Room Temperature]. Pregnancy PROTECT FROM LIGHT. Non-teratogenic Effects Neonates exposed to antipsychotic drugs, during the Retain vial in carton until ready for use. third trimester of pregnancy are at risk for extrapyramidal Vial stoppers do not contain natural rubber latex. and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, * Schooler, N.R.: The Initiation of Long­Term Pharma­ tremor, somnolence, respiratory distress and feed­ cotherapy in Schizophrenia: Dosage and Side Effect ing disorder in these neonates. These complications Comparisons between Oral and Depot Fluphenazine have varied in severity; while in some cases symptoms Pharmakopsych. 9:159­169, 1976. have been self­limited, in other cases neonates have ” x 24” x ” 4

required intensive care unit support and prolonged ⁄ hospitalization. 1 Fluphenazine Decanoate should be used during preg­ nancy only if the potential benefit justifies the potential risk to the fetus. Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. American Possible risk factors for leukopenia/neutrope­ nia include pre­existing low white blood cell count (WBC) and history of drug induced leukopenia/ APPPharmaceutical Pharmaceuticals, LLC neutropenia. Patients with a pre­existing low WBC Schaumburg, IL 60173 or a history of drug induced leukopenia/neutrope­ Partners, Inc. nia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Fluphenazine 45849F Decanoate Injection, USP at the first sign of a decline Revised: September 2010 in WBC in the absence of other causative factors. Pi Font Typesmiths Helvetica (BT) Mathmatical Pi (A) 9/3/10–bw–indd4 CrossTech–63784–Proof 1 CrossTech–63784–Proof M01 Form 45849F No. 4500071745–Job APP–P.O. Decanoate–2 Fluphenazine Helvetica (A) Fonts: 5Z

Patients with neutropenia should be carefully moni­ tored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. 45849F/Revised: September 2010 Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Fluphenazine Decanoate Injection, USP and have their WBC followed until recovery. FLUPHENAZINE DECANOATE Information for Patients INJECTION, USP Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. ADVERSE REACTIONS: Central Nervous System The side effects most frequently reported with phe­ nothiazine compounds are extrapyramidal symptoms including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyper­ reflexia. Muscle rigidity sometimes accompanied by hyperthermia has been reported following use of fluphenazine decanoate. Most often these extrapyra­ midal symptoms are reversible; however, they may be persistent (see below). The frequency of such reactions DESCRIPTION: is related in part to chemical structure: one can expect a Fluphenazine decanoate is the decanoate ester of a higher incidence with fluphenazine decanoate than with trifluoromethyl phenothiazine derivative. It is a highly less potent piperazine derivatives or with straight­chain potent behavior modifier with a markedly extended dura­ phenothiazines such as chlorpromazine. With any given tion of effect and has the following structural formula: phenothiazine derivative, the incidence and severity of such reactions depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants. (CH2)3 N N CH2 CH2 OCO (CH2)8 CH3 Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These N CF reactions can usually be controlled by administration 3 of antiparkinsonian drugs such as Benztropine Mesy late or Intravenous Caffeine and Sodium Benzoate Injection, and by subsequent reduction in dosage. S Tardive Dyskinesia C H F N O S M.W. 591.8 See WARNINGS. The syndrome is characterized by 32 44 3 3 2 involuntary choreoathetoid movements which variously Fluphenazine Decanoate Injection, USP is available involve the tongue, face, mouth, lips, or jaw (e.g., protru­ as a clear, pale yellow solution for intramuscular (IM) or sion of the tongue, puffing of cheeks, puckering of the subcu ta neous (SC) use providing 25 mg fluphen azine mouth, chewing movements), trunk and extrem ities. The decanoate per mL in a sesame oil vehicle with 12 mg severity of the syndrome and the degree of impairment benzyl alcohol as a preservative. produced vary widely. The syndrome may become clinically recognizable CLINICAL PHARMACOLOGY: either during treatment, upon dosage reduction, or The basic effects of fluphenazine decanoate appear to upon withdrawal of treatment. Early detection of tar­ be no different from those of fluphenazine hydrochlo­ dive dyskinesia is important. To increase the likelihood ride, with the exception of duration of action. The ester­ of detecting the syndrome at the earliest possible time, ification of fluphenazine markedly prolongs the drug’s the dosage of the neuroleptic drug should be reduced duration of effect without unduly attenuating its bene­ periodically (if clinically possible) and the patient ficial action. observed for signs of the disorder. This maneuver is Fluphenazine decanoate has activity at all levels of critical, since neuroleptic drugs may mask the signs of the central nervous system (CNS) as well as on multi ple the syndrome. organ systems. The mechanism whereby its therapeutic action is exerted is unknown. Other CNS Effects Fluphenazine differs from other phenothiazine deriv­ Occurrences of neuroleptic malignant syndrome atives in several respects: it is more potent on a mil­ (NMS) have been reported in patients on neurolep­ ligram basis, it has less potentiating effect on CNS tic therapy (see WARNINGS, Neuroleptic Malignant depressants and anesthetics than do some of the Syndrome); leukocytosis, elevated CPK, liver function phenothiazines and appears to be less sedating, and abnormalities, and acute renal failure may also occur it is less likely than some of the older phenothiazines with NMS. to produce hypotension (nevertheless, appropriate Drowsiness or lethargy, if they occur, may necessitate cautions should be observed, see PRECAUTIONS and a reduction in dosage; the induction of a catatonic­ ADVERSE REACTIONS). like state has been known to occur with dosages of fluphenazine far in excess of the recommended INDICATIONS AND USAGE: amounts. As with other phenothiazine compounds, Fluphenazine Decanoate Injection is a long­acting reactivation or aggravation of psychotic processes may parenteral antipsychotic drug intended for use in the be encountered. management of patients requiring prolonged parenteral Phenothiazine derivatives have been known to cause, neuroleptic therapy (e.g., chronic schizophrenics). in some patients, restlessness, excitement, or bizarre Fluphenazine Decanoate Injection has not been dreams. shown effective in the management of behavioral com­ plications in patients with mental retardation. Autonomic Nervous System Hypertension and fluctuations in blood pressure have CONTRAINDICATIONS: been reported with fluphenazine. Phenothiazines are contraindicated in patients with Hypotension has rarely presented a problem with suspected or established subcortical brain damage. fluphenazine. However, patients with pheochromo­ Phenothiazine compounds should not be used in cytoma, cerebral, vascular or renal insufficiency, or a patients receiving large doses of hypnotics. severe cardiac reserve deficiency such as mitral insuf­ Fluphenazine Decanoate Injection is contraindicated ficiency appear to be particularly prone to hypotensive in comatose or severely depressed states. reactions with phenothiazine compounds, and should The presence of blood dyscrasia or liver damage therefore be observed closely when the drug is admin­ precludes the use of fluphenazine decanoate. istered. If severe hypotension should occur, supportive Fluphenazine Decanoate Injection is not intended for measures including the use of intravenous vaso pressor use in children under 12 years of age. drugs should be instituted immediately. Norepinephrine Fluphenazine Decanoate Injection is contraindicated Bitartrate Injection is the most suitable drug for this in patients who have shown hypersensitivity to fluphen­ purpose: epinephrine should not be used since phe­ azine; cross­sensitivity to phenothiazine deriv atives may nothiazine derivatives have been found to reverse its occur. action, resulting in a further lowering of blood pressure. WARNINGS: Autonomic reactions including nausea and loss of Tardive Dyskinesia appetite, salivation, polyuria, perspiration, dry mouth, Tardive dyskinesia, a syndrome consisting of potentially headache, and constipation may occur. Autonomic irreversible, involuntary, dyskinetic movements, may effects can usually be controlled by reducing or tem­ develop in patients treated with neuroleptic (antipsy­ porarily discontinuing dosage. chotic) drugs. Although the prevalence of the syndrome In some patients, phenothiazine derivatives have appears to be highest among the elderly, especially caused blurred vision, glaucoma, bladder paralysis, elderly women, it is impossible to rely upon prevalence fecal impaction, paralytic ileus, tachycardia, or nasal estimates to predict, at the inception of neuroleptic treat­ congestion. ment, which patients are likely to develop the syndrome. Metabolic and Endocrine Whether neuroleptic drug products differ in their poten­ Weight change, peripheral edema, abnormal lactation, tial to cause tardive dyskinesia is unknown. gynecomastia, menstrual irregularities, false results on Both the risk of developing the syndrome and the pregnancy tests, impotency in men and increased libido likelihood that it will become irreversible are believed in women have all been known to occur in some patients to increase as the duration of treatment and the total on phenothiazine therapy. cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can Allergic Reactions develop, although much less commonly, after relatively Skin disorders such as itching, erythema, urticaria, brief treatment periods at low doses. seb orrhea, photosensitivity, eczema and even exfolia­ There is no known treatment for established cases tive dermatitis have been reported with phenothiazine of tardive dyskinesia, although the syndrome may derivatives. The possibility of anaphylactoid reactions remit, partially or completely, if neuroleptic treatment is occurring in some patients should be borne in mind. withdrawn. Neuroleptic treatment, itself, however, may Hematologic suppress (or partially suppress) the signs and symp­ Routine blood counts are advisable during therapy since toms of the syndrome and thereby may possibly mask blood dyscrasias including leukopenia, agranulocytosis, the underlying disease process. The effect that symp­ thrombocytopenic or nonthrombocytopenic purpura, tomatic suppression has upon the long­term course of eosinophilia, and pancytopenia have been observed the syndrome is unknown. with phenothiazine derivatives. Furthermore, if any sore­ Given these considerations, neuroleptics should ness of the mouth, gums, or throat, or any symptoms be prescribed in a manner that is most likely to mini­ of upper respiratory infection occur and confirmatory mize the occurrence of tardive dyskinesia. Chronic leukocyte count indicates cellular depression, therapy neuroleptic treatment should generally be reserved should be discontinued and other appropriate measures for patients who suffer from a chronic illness that, instituted immediately. 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative equally effective, but potentially less Hepatic harmful treatments are not available or appropriate. In Liver damage as manifested by cholestatic jaundice may patients who do require chronic treatment, the small est be encountered, particularly during the first months of dose and the shortest duration of treatment producing therapy; treatment should be discontinued if this occurs. a satisfactory clinical response should be sought. The An increase in cephalin flocculation, sometimes accom­ need for continued treatment should be reassessed panied by alterations in other liver function tests, has periodically. been reported in patients receiving the enanthate ester If signs and symptoms of tardive dyskinesia appear in of fluphenazine (a closely related compound) who have a patient on neuroleptics, drug discontinuation should had no clinical evidence of liver damage. be considered. However, some patients may require Others treatment despite the presence of the syndrome. Sudden, unexpected and unexplained deaths have (For further information about the description of been reported in hospitalized psychotic patients receiv­ tardive dyskinesia and its clinical detection, please ing phenothiazines. Previous brain damage or seizures refer to the sections on PRECAUTIONS, Information may be predisposing factors; high doses should be for Patients, and ADVERSE REACTIONS, Tardive avoided in known seizure patients. Several patients have Dyskinesia.) shown sudden flare­ups of psychotic behavior patterns Neuroleptic Malignant Syndrome (NMS) shortly before death. Autopsy findings have usually A potentially fatal symptom complex sometimes referred revealed acute fulminating pneumonia or pneumonitis, to as Neuroleptic Malignant Syndrome (NMS) has been aspiration of gastric contents, or intramyocardial lesions. reported in association with antipsychotic drugs. Clinical Although this is not a general feature of fluphenazine, manifestations of NMS are hyperpyrexia, muscle rigidity, potentiation of CNS depressants (opiates, analgesics, altered mental status and evidence of autonomic insta­ antihistamines, barbiturates, alcohol) may occur. bility (irregular pulse or blood pressure, tachycardia, The following adverse reactions have also occurred diaphoresis, and cardiac dysrhythmias). with phenothiazine derivatives: Systemic lupus The diagnostic evaluation of patients with this syn­ erythematosus­like syndrome, hypotension severe drome is complicated. In arriving at a diagnosis, it is enough to cause fatal cardiac arrest, altered electro­ important to identify cases where the clinical presen­ cardiographic and electroencephalographic tracings, tation includes both serious medical illness (e.g., pneu­ altered cerebrospinal fluid proteins, cerebral edema, monia, systemic infection, etc.) and untreated or inad­ asthma, laryngeal edema, and angioneurotic edema; equately treated extrapyramidal signs and symptoms with long­term use, skin pigmentation, and lenticular (EPS). Other important considerations in the differential and corneal opacities. diagnosis include central anticholinergic toxicity, heat Injections of fluphenazine decanoate are extremely stroke, drug fever and primary CNS pathology. well tolerated, local tissue reactions occurring only The management of NMS should include 1) imme­ rarely. diate discontinuation of antipsychotic drugs and other DOSAGE AND ADMINISTRATION: drugs not essential to concurrent therapy, 2) intensive Fluphenazine Decanoate Injection may be given IM symptomatic treatment and medical monitoring, and or SC. A dry syringe and needle of at least 21 gauge 3) treatment of any concomitant serious medical prob­ should be used. Use of a wet needle or syringe may lems for which specific treatments are available. There cause the solution to become cloudy. is no general agreement about specific pharmacological To begin therapy with Fluphenazine Decanoate Injec­ treatment regimens for uncomplicated NMS. tion, the following regimens are suggested: If a patient requires antipsychotic drug treatment after For most patients, a dose of 12.5 to 25 mg (0.5 to recovery from NMS, the potential reintroduction of drug 1 mL) may be given to initiate therapy. The onset of therapy should be carefully considered. The patient action generally appears between 24 and 72 hours after should be carefully monitored, since recurrences of injection and the effects of the drug on psychotic NMS have been reported. symptoms becomes significant within 48 to 96 hours. Others Subsequent injections and the dosage interval are deter­ The use of this drug may impair the mental and phys ical mined in accordance with the patient’s response. When abilities required for driving a car or operating heavy administered as maintenance therapy, a single injection machinery. may be effective in controlling schizophrenic symptoms Physicians should be alert to the possibility that severe up to four weeks or longer. The response to a single adverse reactions may occur which require immediate dose has been found to last as long as six weeks in a medical attention. few patients on maintenance therapy. Potentiation of the effects of alcohol may occur with It may be advisable that patients who have no history the use of this drug. of taking phenothiazines should be treated initially with Since there is no adequate experience in children who a shorter­acting form of fluphenazine before admin­ have received this drug, safety and efficacy in children istering the decanoate to determine the patient’s have not been established. response to fluphenazine and to establish appropri­ ate dosage. For psychotic patients who have been Usage In Pregnancy stabilized on a fixed daily dosage of Fluphenazine The safety for the use of this drug during pregnancy Hydrochloride Tablets, USP or Fluphenazine Hydro­ has not been established; therefore, the possible haz­ chloride Elixir, USP conversion of therapy from these ards should be weighed against the potential benefits short­acting oral forms to the long­acting Fluphenazine when administering this drug to pregnant patients. Decanoate Injection may be indicated. PRECAUTIONS: Appropriate dosage of Fluphenazine Decanoate General Injection should be individualized for each patient and Because of the possibility of cross­sensitivity, flu­ responses carefully monitored. No precise formula can phenazine decanoate should be used cautiously in be given to convert to use of Fluphenazine Decano­ patients who have developed cholestatic jaundice, der­ ate Injection; however, a controlled multicentered matoses, or other allergic reactions to phenothiazine study,* in patients receiving oral doses from 5 to derivatives.

60 mg fluphenazine hydrochloride daily, showed that Psychotic patients on large doses of a phenothiazine m 20 mg fluphenazine hydrochloride daily was equivalent drug who are undergoing surgery should be watched to 25 mg (1 mL) of Fluphenazine Decanoate Injection carefully for possible hypotensive phenomena. More­ every three weeks. This represents an approximate con­

over, it should be remembered that reduced amounts version ratio of 12.5 mg (0.5 mL) of decanoate every of anesthetics or CNS depressants may be necessary. three weeks for every 10 mg of fluphenazine hydro­ The effects of atropine may be potentiated in some chloride daily. patients receiving fluphenazine because of added Once conversion to Fluphenazine Decanoate Injection anticholinergic effects. is made, careful clinical monitoring of the patient and Fluphenazine decanoate should be used cautiously appropriate dosage adjustment should be made at the in patients exposed to extreme heat or phosphorus time of each injection. insecticides. Severely agitated patients may be treated initially with The preparation should be used with caution in a rapid­acting phenothiazine compound such as patients with a history of convulsive disorders, since Fluphenazine Hydrochloride Injection—see Package grand mal convulsions have been known to occur. Insert accompanying that product for complete infor­ Use with caution in patients with special medical dis­ mation. When acute symptoms have subsided, 25 mg orders such as mitral insufficiency or other cardiovas­ (1 mL) of Fluphenazine Decanoate Injection may cular disease and pheo chromocytoma. be administered; subsequent dosage is adjusted as The possibility of liver damage, pigmentary retinopa­ necessary. thy, lenticular and corneal deposits, and development ‘‘Poor risk’’ patients (those with known hypersensi­ of irreversible dyskinesia should be remembered tivity to phenothiazines, or with disorders that predis­ when patients are on prolonged therapy. pose to undue reactions): Therapy may be initiated Outside state hospitals or other psychiatric institu­ cautiously with oral or parenteral fluphenazine hydro ­ tions, fluphenazine decanoate should be administered chloride (see Package Inserts accompanying these under the direction of a physician experienced in the products for complete information). When the phar­ clinical use of psychotropic drugs, particularly phe­ macologic effects and an appropriate dosage are nothiazine derivatives. Furthermore, facilities should apparent, an equivalent dose of fluphenazine deca­ be available for periodic checking of hepatic function, noate may be administered. Subsequent dosage ad ­ renal function, and the blood picture. Renal function of just ments are made in accordance with the response patients on long­term therapy should be monitored; if of the patient. blood urea nitrogen (BUN) becomes abnormal, treat­ The optimal amount of the drug and the frequency ment should be discontinued. of administration must be determined for each patient, As with any phenothiazine, the physician should be since dosage requirements have been found to vary alert to the possible development of “silent pneumo­ with clinical circumstances as well as with individual nias” in patients under treatment with fluphenazine response to the drug. decanoate. Dosage should not exceed 100 mg. If doses greater Neuroleptic drugs elevate prolactin levels; the ele­ than 50 mg are deemed necessary, the next dose and vation persists during chronic administration. Tissue succeeding doses should be increased cautiously in culture experiments indicate that approximately one­ increments of 12.5 mg. third of human breast cancers are prolactin dependent Parenteral drug products should be inspected visually in vitro, a factor of potential importance if the prescrip­ for particulate matter and discoloration prior to adminis­ tion of these drugs is contemplated in a patient with a tration, whenever solution and container permit. previously detected breast cancer. Although distur­ HOW SUPPLIED: bances such as galactorrhea, amenorrhea, gyneco­ mastia, and impotence have been reported, the clini­ Product NDC cal significance of elevated serum prolactin levels is No. No. unknown for most patients. An increase in mammary 27205 63323-272-05 Fluphenazine neoplasms has been found in rodents after chronic Decanoate Injection, USP administration of neuroleptic drugs. Neither clinical 25 mg/mL, 5 mL studies nor epidemiologic studies conducted to date, multiple dose, flip- however, have shown an association between chronic top vials individually administration of these drugs and mammary tumorigen­ packaged. esis; the available evidence is considered too limited to Store at 20° to 25°C (68° to 77°F) [see USP Controlled be conclusive at this time. Room Temperature]. Pregnancy PROTECT FROM LIGHT. Non-teratogenic Effects Neonates exposed to antipsychotic drugs, during the Retain vial in carton until ready for use. third trimester of pregnancy are at risk for extrapyramidal Vial stoppers do not contain natural rubber latex. and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, * Schooler, N.R.: The Initiation of Long­Term Pharma­ tremor, somnolence, respiratory distress and feed­ cotherapy in Schizophrenia: Dosage and Side Effect ing disorder in these neonates. These complications Comparisons between Oral and Depot Fluphenazine have varied in severity; while in some cases symptoms Pharmakopsych. 9:159­169, 1976. have been self­limited, in other cases neonates have ” x 24” x ” 4

required intensive care unit support and prolonged ⁄ hospitalization. 1 Fluphenazine Decanoate should be used during preg­ nancy only if the potential benefit justifies the potential risk to the fetus. Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. American Possible risk factors for leukopenia/neutrope­ nia include pre­existing low white blood cell count (WBC) and history of drug induced leukopenia/ APPPharmaceutical Pharmaceuticals, LLC neutropenia. Patients with a pre­existing low WBC Schaumburg, IL 60173 or a history of drug induced leukopenia/neutrope­ Partners, Inc. nia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Fluphenazine 45849F Decanoate Injection, USP at the first sign of a decline Revised: September 2010 in WBC in the absence of other causative factors. Pi Font Typesmiths Helvetica (BT) Mathmatical Pi (A) 9/3/10–bw–indd4 CrossTech–63784–Proof 1 CrossTech–63784–Proof M01 Form 45849F No. 4500071745–Job APP–P.O. Decanoate–2 Fluphenazine Helvetica (A) Fonts: 5Z

Patients with neutropenia should be carefully moni­ tored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. 45849F/Revised: September 2010 Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Fluphenazine Decanoate Injection, USP and have their WBC followed until recovery. FLUPHENAZINE DECANOATE Information for Patients INJECTION, USP Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. ADVERSE REACTIONS: Central Nervous System The side effects most frequently reported with phe­ nothiazine compounds are extrapyramidal symptoms including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyper­ reflexia. Muscle rigidity sometimes accompanied by hyperthermia has been reported following use of fluphenazine decanoate. Most often these extrapyra­ midal symptoms are reversible; however, they may be persistent (see below). The frequency of such reactions DESCRIPTION: is related in part to chemical structure: one can expect a Fluphenazine decanoate is the decanoate ester of a higher incidence with fluphenazine decanoate than with trifluoromethyl phenothiazine derivative. It is a highly less potent piperazine derivatives or with straight­chain potent behavior modifier with a markedly extended dura­ phenothiazines such as chlorpromazine. With any given tion of effect and has the following structural formula: phenothiazine derivative, the incidence and severity of such reactions depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants. (CH2)3 N N CH2 CH2 OCO (CH2)8 CH3 Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These N CF reactions can usually be controlled by administration 3 of antiparkinsonian drugs such as Benztropine Mesy late or Intravenous Caffeine and Sodium Benzoate Injection, and by subsequent reduction in dosage. S Tardive Dyskinesia C H F N O S M.W. 591.8 See WARNINGS. The syndrome is characterized by 32 44 3 3 2 involuntary choreoathetoid movements which variously Fluphenazine Decanoate Injection, USP is available involve the tongue, face, mouth, lips, or jaw (e.g., protru­ as a clear, pale yellow solution for intramuscular (IM) or sion of the tongue, puffing of cheeks, puckering of the subcu ta neous (SC) use providing 25 mg fluphen azine mouth, chewing movements), trunk and extrem ities. The decanoate per mL in a sesame oil vehicle with 12 mg severity of the syndrome and the degree of impairment benzyl alcohol as a preservative. produced vary widely. The syndrome may become clinically recognizable CLINICAL PHARMACOLOGY: either during treatment, upon dosage reduction, or The basic effects of fluphenazine decanoate appear to upon withdrawal of treatment. Early detection of tar­ be no different from those of fluphenazine hydrochlo­ dive dyskinesia is important. To increase the likelihood ride, with the exception of duration of action. The ester­ of detecting the syndrome at the earliest possible time, ification of fluphenazine markedly prolongs the drug’s the dosage of the neuroleptic drug should be reduced duration of effect without unduly attenuating its bene­ periodically (if clinically possible) and the patient ficial action. observed for signs of the disorder. This maneuver is Fluphenazine decanoate has activity at all levels of critical, since neuroleptic drugs may mask the signs of the central nervous system (CNS) as well as on multi ple the syndrome. organ systems. The mechanism whereby its therapeutic action is exerted is unknown. Other CNS Effects Fluphenazine differs from other phenothiazine deriv­ Occurrences of neuroleptic malignant syndrome atives in several respects: it is more potent on a mil­ (NMS) have been reported in patients on neurolep­ ligram basis, it has less potentiating effect on CNS tic therapy (see WARNINGS, Neuroleptic Malignant depressants and anesthetics than do some of the Syndrome); leukocytosis, elevated CPK, liver function phenothiazines and appears to be less sedating, and abnormalities, and acute renal failure may also occur it is less likely than some of the older phenothiazines with NMS. to produce hypotension (nevertheless, appropriate Drowsiness or lethargy, if they occur, may necessitate cautions should be observed, see PRECAUTIONS and a reduction in dosage; the induction of a catatonic­ ADVERSE REACTIONS). like state has been known to occur with dosages of fluphenazine far in excess of the recommended INDICATIONS AND USAGE: amounts. As with other phenothiazine compounds, Fluphenazine Decanoate Injection is a long­acting reactivation or aggravation of psychotic processes may parenteral antipsychotic drug intended for use in the be encountered. management of patients requiring prolonged parenteral Phenothiazine derivatives have been known to cause, neuroleptic therapy (e.g., chronic schizophrenics). in some patients, restlessness, excitement, or bizarre Fluphenazine Decanoate Injection has not been dreams. shown effective in the management of behavioral com­ plications in patients with mental retardation. Autonomic Nervous System Hypertension and fluctuations in blood pressure have CONTRAINDICATIONS: been reported with fluphenazine. Phenothiazines are contraindicated in patients with Hypotension has rarely presented a problem with suspected or established subcortical brain damage. fluphenazine. However, patients with pheochromo­ Phenothiazine compounds should not be used in cytoma, cerebral, vascular or renal insufficiency, or a patients receiving large doses of hypnotics. severe cardiac reserve deficiency such as mitral insuf­ Fluphenazine Decanoate Injection is contraindicated ficiency appear to be particularly prone to hypotensive in comatose or severely depressed states. reactions with phenothiazine compounds, and should The presence of blood dyscrasia or liver damage therefore be observed closely when the drug is admin­ precludes the use of fluphenazine decanoate. istered. If severe hypotension should occur, supportive Fluphenazine Decanoate Injection is not intended for measures including the use of intravenous vaso pressor use in children under 12 years of age. drugs should be instituted immediately. Norepinephrine Fluphenazine Decanoate Injection is contraindicated Bitartrate Injection is the most suitable drug for this in patients who have shown hypersensitivity to fluphen­ purpose: epinephrine should not be used since phe­ azine; cross­sensitivity to phenothiazine deriv atives may nothiazine derivatives have been found to reverse its occur. action, resulting in a further lowering of blood pressure. WARNINGS: Autonomic reactions including nausea and loss of Tardive Dyskinesia appetite, salivation, polyuria, perspiration, dry mouth, Tardive dyskinesia, a syndrome consisting of potentially headache, and constipation may occur. Autonomic irreversible, involuntary, dyskinetic movements, may effects can usually be controlled by reducing or tem­ develop in patients treated with neuroleptic (antipsy­ porarily discontinuing dosage. chotic) drugs. Although the prevalence of the syndrome In some patients, phenothiazine derivatives have appears to be highest among the elderly, especially caused blurred vision, glaucoma, bladder paralysis, elderly women, it is impossible to rely upon prevalence fecal impaction, paralytic ileus, tachycardia, or nasal estimates to predict, at the inception of neuroleptic treat­ congestion. ment, which patients are likely to develop the syndrome. Metabolic and Endocrine Whether neuroleptic drug products differ in their poten­ Weight change, peripheral edema, abnormal lactation, tial to cause tardive dyskinesia is unknown. gynecomastia, menstrual irregularities, false results on Both the risk of developing the syndrome and the pregnancy tests, impotency in men and increased libido likelihood that it will become irreversible are believed in women have all been known to occur in some patients to increase as the duration of treatment and the total on phenothiazine therapy. cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can Allergic Reactions develop, although much less commonly, after relatively Skin disorders such as itching, erythema, urticaria, brief treatment periods at low doses. seb orrhea, photosensitivity, eczema and even exfolia­ There is no known treatment for established cases tive dermatitis have been reported with phenothiazine of tardive dyskinesia, although the syndrome may derivatives. The possibility of anaphylactoid reactions remit, partially or completely, if neuroleptic treatment is occurring in some patients should be borne in mind. withdrawn. Neuroleptic treatment, itself, however, may Hematologic suppress (or partially suppress) the signs and symp­ Routine blood counts are advisable during therapy since toms of the syndrome and thereby may possibly mask blood dyscrasias including leukopenia, agranulocytosis, the underlying disease process. The effect that symp­ thrombocytopenic or nonthrombocytopenic purpura, tomatic suppression has upon the long­term course of eosinophilia, and pancytopenia have been observed the syndrome is unknown. with phenothiazine derivatives. Furthermore, if any sore­ Given these considerations, neuroleptics should ness of the mouth, gums, or throat, or any symptoms be prescribed in a manner that is most likely to mini­ of upper respiratory infection occur and confirmatory mize the occurrence of tardive dyskinesia. Chronic leukocyte count indicates cellular depression, therapy neuroleptic treatment should generally be reserved should be discontinued and other appropriate measures for patients who suffer from a chronic illness that, instituted immediately. 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative equally effective, but potentially less Hepatic harmful treatments are not available or appropriate. In Liver damage as manifested by cholestatic jaundice may patients who do require chronic treatment, the small est be encountered, particularly during the first months of dose and the shortest duration of treatment producing therapy; treatment should be discontinued if this occurs. a satisfactory clinical response should be sought. The An increase in cephalin flocculation, sometimes accom­ need for continued treatment should be reassessed panied by alterations in other liver function tests, has periodically. been reported in patients receiving the enanthate ester If signs and symptoms of tardive dyskinesia appear in of fluphenazine (a closely related compound) who have a patient on neuroleptics, drug discontinuation should had no clinical evidence of liver damage. be considered. However, some patients may require Others treatment despite the presence of the syndrome. Sudden, unexpected and unexplained deaths have (For further information about the description of been reported in hospitalized psychotic patients receiv­ tardive dyskinesia and its clinical detection, please ing phenothiazines. Previous brain damage or seizures refer to the sections on PRECAUTIONS, Information may be predisposing factors; high doses should be for Patients, and ADVERSE REACTIONS, Tardive avoided in known seizure patients. Several patients have Dyskinesia.) shown sudden flare­ups of psychotic behavior patterns Neuroleptic Malignant Syndrome (NMS) shortly before death. Autopsy findings have usually A potentially fatal symptom complex sometimes referred revealed acute fulminating pneumonia or pneumonitis, to as Neuroleptic Malignant Syndrome (NMS) has been aspiration of gastric contents, or intramyocardial lesions. reported in association with antipsychotic drugs. Clinical Although this is not a general feature of fluphenazine, manifestations of NMS are hyperpyrexia, muscle rigidity, potentiation of CNS depressants (opiates, analgesics, altered mental status and evidence of autonomic insta­ antihistamines, barbiturates, alcohol) may occur. bility (irregular pulse or blood pressure, tachycardia, The following adverse reactions have also occurred diaphoresis, and cardiac dysrhythmias). with phenothiazine derivatives: Systemic lupus The diagnostic evaluation of patients with this syn­ erythematosus­like syndrome, hypotension severe drome is complicated. In arriving at a diagnosis, it is enough to cause fatal cardiac arrest, altered electro­ important to identify cases where the clinical presen­ cardiographic and electroencephalographic tracings, tation includes both serious medical illness (e.g., pneu­ altered cerebrospinal fluid proteins, cerebral edema, monia, systemic infection, etc.) and untreated or inad­ asthma, laryngeal edema, and angioneurotic edema; equately treated extrapyramidal signs and symptoms with long­term use, skin pigmentation, and lenticular (EPS). Other important considerations in the differential and corneal opacities. diagnosis include central anticholinergic toxicity, heat Injections of fluphenazine decanoate are extremely stroke, drug fever and primary CNS pathology. well tolerated, local tissue reactions occurring only The management of NMS should include 1) imme­ rarely. diate discontinuation of antipsychotic drugs and other DOSAGE AND ADMINISTRATION: drugs not essential to concurrent therapy, 2) intensive Fluphenazine Decanoate Injection may be given IM symptomatic treatment and medical monitoring, and or SC. A dry syringe and needle of at least 21 gauge 3) treatment of any concomitant serious medical prob­ should be used. Use of a wet needle or syringe may lems for which specific treatments are available. There cause the solution to become cloudy. is no general agreement about specific pharmacological To begin therapy with Fluphenazine Decanoate Injec­ treatment regimens for uncomplicated NMS. tion, the following regimens are suggested: If a patient requires antipsychotic drug treatment after For most patients, a dose of 12.5 to 25 mg (0.5 to recovery from NMS, the potential reintroduction of drug 1 mL) may be given to initiate therapy. The onset of therapy should be carefully considered. The patient action generally appears between 24 and 72 hours after should be carefully monitored, since recurrences of injection and the effects of the drug on psychotic NMS have been reported. symptoms becomes significant within 48 to 96 hours. Others Subsequent injections and the dosage interval are deter­ The use of this drug may impair the mental and phys ical mined in accordance with the patient’s response. When abilities required for driving a car or operating heavy administered as maintenance therapy, a single injection machinery. may be effective in controlling schizophrenic symptoms Physicians should be alert to the possibility that severe up to four weeks or longer. The response to a single adverse reactions may occur which require immediate dose has been found to last as long as six weeks in a medical attention. few patients on maintenance therapy. Potentiation of the effects of alcohol may occur with It may be advisable that patients who have no history the use of this drug. of taking phenothiazines should be treated initially with Since there is no adequate experience in children who a shorter­acting form of fluphenazine before admin­ have received this drug, safety and efficacy in children istering the decanoate to determine the patient’s have not been established. response to fluphenazine and to establish appropri­ ate dosage. For psychotic patients who have been Usage In Pregnancy stabilized on a fixed daily dosage of Fluphenazine The safety for the use of this drug during pregnancy Hydrochloride Tablets, USP or Fluphenazine Hydro­ has not been established; therefore, the possible haz­ chloride Elixir, USP conversion of therapy from these ards should be weighed against the potential benefits short­acting oral forms to the long­acting Fluphenazine when administering this drug to pregnant patients. Decanoate Injection may be indicated. PRECAUTIONS: Appropriate dosage of Fluphenazine Decanoate General Injection should be individualized for each patient and Because of the possibility of cross­sensitivity, flu­ responses carefully monitored. No precise formula can phenazine decanoate should be used cautiously in be given to convert to use of Fluphenazine Decano­ patients who have developed cholestatic jaundice, der­ ate Injection; however, a controlled multicentered matoses, or other allergic reactions to phenothiazine study,* in patients receiving oral doses from 5 to derivatives.

60 mg fluphenazine hydrochloride daily, showed that Psychotic patients on large doses of a phenothiazine m 20 mg fluphenazine hydrochloride daily was equivalent drug who are undergoing surgery should be watched to 25 mg (1 mL) of Fluphenazine Decanoate Injection carefully for possible hypotensive phenomena. More­ every three weeks. This represents an approximate con­

over, it should be remembered that reduced amounts version ratio of 12.5 mg (0.5 mL) of decanoate every of anesthetics or CNS depressants may be necessary. three weeks for every 10 mg of fluphenazine hydro­ The effects of atropine may be potentiated in some chloride daily. patients receiving fluphenazine because of added Once conversion to Fluphenazine Decanoate Injection anticholinergic effects. is made, careful clinical monitoring of the patient and Fluphenazine decanoate should be used cautiously appropriate dosage adjustment should be made at the in patients exposed to extreme heat or phosphorus time of each injection. insecticides. Severely agitated patients may be treated initially with The preparation should be used with caution in a rapid­acting phenothiazine compound such as patients with a history of convulsive disorders, since Fluphenazine Hydrochloride Injection—see Package grand mal convulsions have been known to occur. Insert accompanying that product for complete infor­ Use with caution in patients with special medical dis­ mation. When acute symptoms have subsided, 25 mg orders such as mitral insufficiency or other cardiovas­ (1 mL) of Fluphenazine Decanoate Injection may cular disease and pheo chromocytoma. be administered; subsequent dosage is adjusted as The possibility of liver damage, pigmentary retinopa­ necessary. thy, lenticular and corneal deposits, and development ‘‘Poor risk’’ patients (those with known hypersensi­ of irreversible dyskinesia should be remembered tivity to phenothiazines, or with disorders that predis­ when patients are on prolonged therapy. pose to undue reactions): Therapy may be initiated Outside state hospitals or other psychiatric institu­ cautiously with oral or parenteral fluphenazine hydro ­ tions, fluphenazine decanoate should be administered chloride (see Package Inserts accompanying these under the direction of a physician experienced in the products for complete information). When the phar­ clinical use of psychotropic drugs, particularly phe­ macologic effects and an appropriate dosage are nothiazine derivatives. Furthermore, facilities should apparent, an equivalent dose of fluphenazine deca­ be available for periodic checking of hepatic function, noate may be administered. Subsequent dosage ad ­ renal function, and the blood picture. Renal function of just ments are made in accordance with the response patients on long­term therapy should be monitored; if of the patient. blood urea nitrogen (BUN) becomes abnormal, treat­ The optimal amount of the drug and the frequency ment should be discontinued. of administration must be determined for each patient, As with any phenothiazine, the physician should be since dosage requirements have been found to vary alert to the possible development of “silent pneumo­ with clinical circumstances as well as with individual nias” in patients under treatment with fluphenazine response to the drug. decanoate. Dosage should not exceed 100 mg. If doses greater Neuroleptic drugs elevate prolactin levels; the ele­ than 50 mg are deemed necessary, the next dose and vation persists during chronic administration. Tissue succeeding doses should be increased cautiously in culture experiments indicate that approximately one­ increments of 12.5 mg. third of human breast cancers are prolactin dependent Parenteral drug products should be inspected visually in vitro, a factor of potential importance if the prescrip­ for particulate matter and discoloration prior to adminis­ tion of these drugs is contemplated in a patient with a tration, whenever solution and container permit. previously detected breast cancer. Although distur­ HOW SUPPLIED: bances such as galactorrhea, amenorrhea, gyneco­ mastia, and impotence have been reported, the clini­ Product NDC cal significance of elevated serum prolactin levels is No. No. unknown for most patients. An increase in mammary 27205 63323-272-05 Fluphenazine neoplasms has been found in rodents after chronic Decanoate Injection, USP administration of neuroleptic drugs. Neither clinical 25 mg/mL, 5 mL studies nor epidemiologic studies conducted to date, multiple dose, flip- however, have shown an association between chronic top vials individually administration of these drugs and mammary tumorigen­ packaged. esis; the available evidence is considered too limited to Store at 20° to 25°C (68° to 77°F) [see USP Controlled be conclusive at this time. Room Temperature]. Pregnancy PROTECT FROM LIGHT. Non-teratogenic Effects Neonates exposed to antipsychotic drugs, during the Retain vial in carton until ready for use. third trimester of pregnancy are at risk for extrapyramidal Vial stoppers do not contain natural rubber latex. and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, * Schooler, N.R.: The Initiation of Long­Term Pharma­ tremor, somnolence, respiratory distress and feed­ cotherapy in Schizophrenia: Dosage and Side Effect ing disorder in these neonates. These complications Comparisons between Oral and Depot Fluphenazine have varied in severity; while in some cases symptoms Pharmakopsych. 9:159­169, 1976. have been self­limited, in other cases neonates have ” x 24” x ” 4

required intensive care unit support and prolonged ⁄ hospitalization. 1 Fluphenazine Decanoate should be used during preg­ nancy only if the potential benefit justifies the potential risk to the fetus. Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. American Possible risk factors for leukopenia/neutrope­ nia include pre­existing low white blood cell count (WBC) and history of drug induced leukopenia/ APPPharmaceutical Pharmaceuticals, LLC neutropenia. Patients with a pre­existing low WBC Schaumburg, IL 60173 or a history of drug induced leukopenia/neutrope­ Partners, Inc. nia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Fluphenazine 45849F Decanoate Injection, USP at the first sign of a decline Revised: September 2010 in WBC in the absence of other causative factors. Pi Font Typesmiths Helvetica (BT) Mathmatical Pi (A) 9/3/10–bw–indd4 CrossTech–63784–Proof 1 CrossTech–63784–Proof M01 Form 45849F No. 4500071745–Job APP–P.O. Decanoate–2 Fluphenazine Helvetica (A) Fonts: 5Z

Patients with neutropenia should be carefully moni­ tored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. 45849F/Revised: September 2010 Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Fluphenazine Decanoate Injection, USP and have their WBC followed until recovery. FLUPHENAZINE DECANOATE Information for Patients INJECTION, USP Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided. ADVERSE REACTIONS: Central Nervous System The side effects most frequently reported with phe­ nothiazine compounds are extrapyramidal symptoms including pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyper­ reflexia. Muscle rigidity sometimes accompanied by hyperthermia has been reported following use of fluphenazine decanoate. Most often these extrapyra­ midal symptoms are reversible; however, they may be persistent (see below). The frequency of such reactions DESCRIPTION: is related in part to chemical structure: one can expect a Fluphenazine decanoate is the decanoate ester of a higher incidence with fluphenazine decanoate than with trifluoromethyl phenothiazine derivative. It is a highly less potent piperazine derivatives or with straight­chain potent behavior modifier with a markedly extended dura­ phenothiazines such as chlorpromazine. With any given tion of effect and has the following structural formula: phenothiazine derivative, the incidence and severity of such reactions depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants. (CH2)3 N N CH2 CH2 OCO (CH2)8 CH3 Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These N CF reactions can usually be controlled by administration 3 of antiparkinsonian drugs such as Benztropine Mesy late or Intravenous Caffeine and Sodium Benzoate Injection, and by subsequent reduction in dosage. S Tardive Dyskinesia C H F N O S M.W. 591.8 See WARNINGS. The syndrome is characterized by 32 44 3 3 2 involuntary choreoathetoid movements which variously Fluphenazine Decanoate Injection, USP is available involve the tongue, face, mouth, lips, or jaw (e.g., protru­ as a clear, pale yellow solution for intramuscular (IM) or sion of the tongue, puffing of cheeks, puckering of the subcu ta neous (SC) use providing 25 mg fluphen azine mouth, chewing movements), trunk and extrem ities. The decanoate per mL in a sesame oil vehicle with 12 mg severity of the syndrome and the degree of impairment benzyl alcohol as a preservative. produced vary widely. The syndrome may become clinically recognizable CLINICAL PHARMACOLOGY: either during treatment, upon dosage reduction, or The basic effects of fluphenazine decanoate appear to upon withdrawal of treatment. Early detection of tar­ be no different from those of fluphenazine hydrochlo­ dive dyskinesia is important. To increase the likelihood ride, with the exception of duration of action. The ester­ of detecting the syndrome at the earliest possible time, ification of fluphenazine markedly prolongs the drug’s the dosage of the neuroleptic drug should be reduced duration of effect without unduly attenuating its bene­ periodically (if clinically possible) and the patient ficial action. observed for signs of the disorder. This maneuver is Fluphenazine decanoate has activity at all levels of critical, since neuroleptic drugs may mask the signs of the central nervous system (CNS) as well as on multi ple the syndrome. organ systems. The mechanism whereby its therapeutic action is exerted is unknown. Other CNS Effects Fluphenazine differs from other phenothiazine deriv­ Occurrences of neuroleptic malignant syndrome atives in several respects: it is more potent on a mil­ (NMS) have been reported in patients on neurolep­ ligram basis, it has less potentiating effect on CNS tic therapy (see WARNINGS, Neuroleptic Malignant depressants and anesthetics than do some of the Syndrome); leukocytosis, elevated CPK, liver function phenothiazines and appears to be less sedating, and abnormalities, and acute renal failure may also occur it is less likely than some of the older phenothiazines with NMS. to produce hypotension (nevertheless, appropriate Drowsiness or lethargy, if they occur, may necessitate cautions should be observed, see PRECAUTIONS and a reduction in dosage; the induction of a catatonic­ ADVERSE REACTIONS). like state has been known to occur with dosages of fluphenazine far in excess of the recommended INDICATIONS AND USAGE: amounts. As with other phenothiazine compounds, Fluphenazine Decanoate Injection is a long­acting reactivation or aggravation of psychotic processes may parenteral antipsychotic drug intended for use in the be encountered. management of patients requiring prolonged parenteral Phenothiazine derivatives have been known to cause, neuroleptic therapy (e.g., chronic schizophrenics). in some patients, restlessness, excitement, or bizarre Fluphenazine Decanoate Injection has not been dreams. shown effective in the management of behavioral com­ plications in patients with mental retardation. Autonomic Nervous System Hypertension and fluctuations in blood pressure have CONTRAINDICATIONS: been reported with fluphenazine. Phenothiazines are contraindicated in patients with Hypotension has rarely presented a problem with suspected or established subcortical brain damage. fluphenazine. However, patients with pheochromo­ Phenothiazine compounds should not be used in cytoma, cerebral, vascular or renal insufficiency, or a patients receiving large doses of hypnotics. severe cardiac reserve deficiency such as mitral insuf­ Fluphenazine Decanoate Injection is contraindicated ficiency appear to be particularly prone to hypotensive in comatose or severely depressed states. reactions with phenothiazine compounds, and should The presence of blood dyscrasia or liver damage therefore be observed closely when the drug is admin­ precludes the use of fluphenazine decanoate. istered. If severe hypotension should occur, supportive Fluphenazine Decanoate Injection is not intended for measures including the use of intravenous vaso pressor use in children under 12 years of age. drugs should be instituted immediately. Norepinephrine Fluphenazine Decanoate Injection is contraindicated Bitartrate Injection is the most suitable drug for this in patients who have shown hypersensitivity to fluphen­ purpose: epinephrine should not be used since phe­ azine; cross­sensitivity to phenothiazine deriv atives may nothiazine derivatives have been found to reverse its occur. action, resulting in a further lowering of blood pressure. WARNINGS: Autonomic reactions including nausea and loss of Tardive Dyskinesia appetite, salivation, polyuria, perspiration, dry mouth, Tardive dyskinesia, a syndrome consisting of potentially headache, and constipation may occur. Autonomic irreversible, involuntary, dyskinetic movements, may effects can usually be controlled by reducing or tem­ develop in patients treated with neuroleptic (antipsy­ porarily discontinuing dosage. chotic) drugs. Although the prevalence of the syndrome In some patients, phenothiazine derivatives have appears to be highest among the elderly, especially caused blurred vision, glaucoma, bladder paralysis, elderly women, it is impossible to rely upon prevalence fecal impaction, paralytic ileus, tachycardia, or nasal estimates to predict, at the inception of neuroleptic treat­ congestion. ment, which patients are likely to develop the syndrome. Metabolic and Endocrine Whether neuroleptic drug products differ in their poten­ Weight change, peripheral edema, abnormal lactation, tial to cause tardive dyskinesia is unknown. gynecomastia, menstrual irregularities, false results on Both the risk of developing the syndrome and the pregnancy tests, impotency in men and increased libido likelihood that it will become irreversible are believed in women have all been known to occur in some patients to increase as the duration of treatment and the total on phenothiazine therapy. cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can Allergic Reactions develop, although much less commonly, after relatively Skin disorders such as itching, erythema, urticaria, brief treatment periods at low doses. seb orrhea, photosensitivity, eczema and even exfolia­ There is no known treatment for established cases tive dermatitis have been reported with phenothiazine of tardive dyskinesia, although the syndrome may derivatives. The possibility of anaphylactoid reactions remit, partially or completely, if neuroleptic treatment is occurring in some patients should be borne in mind. withdrawn. Neuroleptic treatment, itself, however, may Hematologic suppress (or partially suppress) the signs and symp­ Routine blood counts are advisable during therapy since toms of the syndrome and thereby may possibly mask blood dyscrasias including leukopenia, agranulocytosis, the underlying disease process. The effect that symp­ thrombocytopenic or nonthrombocytopenic purpura, tomatic suppression has upon the long­term course of eosinophilia, and pancytopenia have been observed the syndrome is unknown. with phenothiazine derivatives. Furthermore, if any sore­ Given these considerations, neuroleptics should ness of the mouth, gums, or throat, or any symptoms be prescribed in a manner that is most likely to mini­ of upper respiratory infection occur and confirmatory mize the occurrence of tardive dyskinesia. Chronic leukocyte count indicates cellular depression, therapy neuroleptic treatment should generally be reserved should be discontinued and other appropriate measures for patients who suffer from a chronic illness that, instituted immediately. 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative equally effective, but potentially less Hepatic harmful treatments are not available or appropriate. In Liver damage as manifested by cholestatic jaundice may patients who do require chronic treatment, the small est be encountered, particularly during the first months of dose and the shortest duration of treatment producing therapy; treatment should be discontinued if this occurs. a satisfactory clinical response should be sought. The An increase in cephalin flocculation, sometimes accom­ need for continued treatment should be reassessed panied by alterations in other liver function tests, has periodically. been reported in patients receiving the enanthate ester If signs and symptoms of tardive dyskinesia appear in of fluphenazine (a closely related compound) who have a patient on neuroleptics, drug discontinuation should had no clinical evidence of liver damage. be considered. However, some patients may require Others treatment despite the presence of the syndrome. Sudden, unexpected and unexplained deaths have (For further information about the description of been reported in hospitalized psychotic patients receiv­ tardive dyskinesia and its clinical detection, please ing phenothiazines. Previous brain damage or seizures refer to the sections on PRECAUTIONS, Information may be predisposing factors; high doses should be for Patients, and ADVERSE REACTIONS, Tardive avoided in known seizure patients. Several patients have Dyskinesia.) shown sudden flare­ups of psychotic behavior patterns Neuroleptic Malignant Syndrome (NMS) shortly before death. Autopsy findings have usually A potentially fatal symptom complex sometimes referred revealed acute fulminating pneumonia or pneumonitis, to as Neuroleptic Malignant Syndrome (NMS) has been aspiration of gastric contents, or intramyocardial lesions. reported in association with antipsychotic drugs. Clinical Although this is not a general feature of fluphenazine, manifestations of NMS are hyperpyrexia, muscle rigidity, potentiation of CNS depressants (opiates, analgesics, altered mental status and evidence of autonomic insta­ antihistamines, barbiturates, alcohol) may occur. bility (irregular pulse or blood pressure, tachycardia, The following adverse reactions have also occurred diaphoresis, and cardiac dysrhythmias). with phenothiazine derivatives: Systemic lupus The diagnostic evaluation of patients with this syn­ erythematosus­like syndrome, hypotension severe drome is complicated. In arriving at a diagnosis, it is enough to cause fatal cardiac arrest, altered electro­ important to identify cases where the clinical presen­ cardiographic and electroencephalographic tracings, tation includes both serious medical illness (e.g., pneu­ altered cerebrospinal fluid proteins, cerebral edema, monia, systemic infection, etc.) and untreated or inad­ asthma, laryngeal edema, and angioneurotic edema; equately treated extrapyramidal signs and symptoms with long­term use, skin pigmentation, and lenticular (EPS). Other important considerations in the differential and corneal opacities. diagnosis include central anticholinergic toxicity, heat Injections of fluphenazine decanoate are extremely stroke, drug fever and primary CNS pathology. well tolerated, local tissue reactions occurring only The management of NMS should include 1) imme­ rarely. diate discontinuation of antipsychotic drugs and other DOSAGE AND ADMINISTRATION: drugs not essential to concurrent therapy, 2) intensive Fluphenazine Decanoate Injection may be given IM symptomatic treatment and medical monitoring, and or SC. A dry syringe and needle of at least 21 gauge 3) treatment of any concomitant serious medical prob­ should be used. Use of a wet needle or syringe may lems for which specific treatments are available. There cause the solution to become cloudy. is no general agreement about specific pharmacological To begin therapy with Fluphenazine Decanoate Injec­ treatment regimens for uncomplicated NMS. tion, the following regimens are suggested: If a patient requires antipsychotic drug treatment after For most patients, a dose of 12.5 to 25 mg (0.5 to recovery from NMS, the potential reintroduction of drug 1 mL) may be given to initiate therapy. The onset of therapy should be carefully considered. The patient action generally appears between 24 and 72 hours after should be carefully monitored, since recurrences of injection and the effects of the drug on psychotic NMS have been reported. symptoms becomes significant within 48 to 96 hours. Others Subsequent injections and the dosage interval are deter­ The use of this drug may impair the mental and phys ical mined in accordance with the patient’s response. When abilities required for driving a car or operating heavy administered as maintenance therapy, a single injection machinery. may be effective in controlling schizophrenic symptoms Physicians should be alert to the possibility that severe up to four weeks or longer. The response to a single adverse reactions may occur which require immediate dose has been found to last as long as six weeks in a medical attention. few patients on maintenance therapy. Potentiation of the effects of alcohol may occur with It may be advisable that patients who have no history the use of this drug. of taking phenothiazines should be treated initially with Since there is no adequate experience in children who a shorter­acting form of fluphenazine before admin­ have received this drug, safety and efficacy in children istering the decanoate to determine the patient’s have not been established. response to fluphenazine and to establish appropri­ ate dosage. For psychotic patients who have been Usage In Pregnancy stabilized on a fixed daily dosage of Fluphenazine The safety for the use of this drug during pregnancy Hydrochloride Tablets, USP or Fluphenazine Hydro­ has not been established; therefore, the possible haz­ chloride Elixir, USP conversion of therapy from these ards should be weighed against the potential benefits short­acting oral forms to the long­acting Fluphenazine when administering this drug to pregnant patients. Decanoate Injection may be indicated. PRECAUTIONS: Appropriate dosage of Fluphenazine Decanoate General Injection should be individualized for each patient and Because of the possibility of cross­sensitivity, flu­ responses carefully monitored. No precise formula can phenazine decanoate should be used cautiously in be given to convert to use of Fluphenazine Decano­ patients who have developed cholestatic jaundice, der­ ate Injection; however, a controlled multicentered matoses, or other allergic reactions to phenothiazine study,* in patients receiving oral doses from 5 to derivatives.

60 mg fluphenazine hydrochloride daily, showed that Psychotic patients on large doses of a phenothiazine m 20 mg fluphenazine hydrochloride daily was equivalent drug who are undergoing surgery should be watched to 25 mg (1 mL) of Fluphenazine Decanoate Injection carefully for possible hypotensive phenomena. More­ every three weeks. This represents an approximate con­

over, it should be remembered that reduced amounts version ratio of 12.5 mg (0.5 mL) of decanoate every of anesthetics or CNS depressants may be necessary. three weeks for every 10 mg of fluphenazine hydro­ The effects of atropine may be potentiated in some chloride daily. patients receiving fluphenazine because of added Once conversion to Fluphenazine Decanoate Injection anticholinergic effects. is made, careful clinical monitoring of the patient and Fluphenazine decanoate should be used cautiously appropriate dosage adjustment should be made at the in patients exposed to extreme heat or phosphorus time of each injection. insecticides. Severely agitated patients may be treated initially with The preparation should be used with caution in a rapid­acting phenothiazine compound such as patients with a history of convulsive disorders, since Fluphenazine Hydrochloride Injection—see Package grand mal convulsions have been known to occur. Insert accompanying that product for complete infor­ Use with caution in patients with special medical dis­ mation. When acute symptoms have subsided, 25 mg orders such as mitral insufficiency or other cardiovas­ (1 mL) of Fluphenazine Decanoate Injection may cular disease and pheo chromocytoma. be administered; subsequent dosage is adjusted as The possibility of liver damage, pigmentary retinopa­ necessary. thy, lenticular and corneal deposits, and development ‘‘Poor risk’’ patients (those with known hypersensi­ of irreversible dyskinesia should be remembered tivity to phenothiazines, or with disorders that predis­ when patients are on prolonged therapy. pose to undue reactions): Therapy may be initiated Outside state hospitals or other psychiatric institu­ cautiously with oral or parenteral fluphenazine hydro ­ tions, fluphenazine decanoate should be administered chloride (see Package Inserts accompanying these under the direction of a physician experienced in the products for complete information). When the phar­ clinical use of psychotropic drugs, particularly phe­ macologic effects and an appropriate dosage are nothiazine derivatives. Furthermore, facilities should apparent, an equivalent dose of fluphenazine deca­ be available for periodic checking of hepatic function, noate may be administered. Subsequent dosage ad ­ renal function, and the blood picture. Renal function of just ments are made in accordance with the response patients on long­term therapy should be monitored; if of the patient. blood urea nitrogen (BUN) becomes abnormal, treat­ The optimal amount of the drug and the frequency ment should be discontinued. of administration must be determined for each patient, As with any phenothiazine, the physician should be since dosage requirements have been found to vary alert to the possible development of “silent pneumo­ with clinical circumstances as well as with individual nias” in patients under treatment with fluphenazine response to the drug. decanoate. Dosage should not exceed 100 mg. If doses greater Neuroleptic drugs elevate prolactin levels; the ele­ than 50 mg are deemed necessary, the next dose and vation persists during chronic administration. Tissue succeeding doses should be increased cautiously in culture experiments indicate that approximately one­ increments of 12.5 mg. third of human breast cancers are prolactin dependent Parenteral drug products should be inspected visually in vitro, a factor of potential importance if the prescrip­ for particulate matter and discoloration prior to adminis­ tion of these drugs is contemplated in a patient with a tration, whenever solution and container permit. previously detected breast cancer. Although distur­ HOW SUPPLIED: bances such as galactorrhea, amenorrhea, gyneco­ mastia, and impotence have been reported, the clini­ Product NDC cal significance of elevated serum prolactin levels is No. No. unknown for most patients. An increase in mammary 27205 63323-272-05 Fluphenazine neoplasms has been found in rodents after chronic Decanoate Injection, USP administration of neuroleptic drugs. Neither clinical 25 mg/mL, 5 mL studies nor epidemiologic studies conducted to date, multiple dose, flip- however, have shown an association between chronic top vials individually administration of these drugs and mammary tumorigen­ packaged. esis; the available evidence is considered too limited to Store at 20° to 25°C (68° to 77°F) [see USP Controlled be conclusive at this time. Room Temperature]. Pregnancy PROTECT FROM LIGHT. Non-teratogenic Effects Neonates exposed to antipsychotic drugs, during the Retain vial in carton until ready for use. third trimester of pregnancy are at risk for extrapyramidal Vial stoppers do not contain natural rubber latex. and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, * Schooler, N.R.: The Initiation of Long­Term Pharma­ tremor, somnolence, respiratory distress and feed­ cotherapy in Schizophrenia: Dosage and Side Effect ing disorder in these neonates. These complications Comparisons between Oral and Depot Fluphenazine have varied in severity; while in some cases symptoms Pharmakopsych. 9:159­169, 1976. have been self­limited, in other cases neonates have ” x 24” x ” 4

required intensive care unit support and prolonged ⁄ hospitalization. 1 Fluphenazine Decanoate should be used during preg­ nancy only if the potential benefit justifies the potential risk to the fetus. Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. American Possible risk factors for leukopenia/neutrope­ nia include pre­existing low white blood cell count (WBC) and history of drug induced leukopenia/ APPPharmaceutical Pharmaceuticals, LLC neutropenia. Patients with a pre­existing low WBC Schaumburg, IL 60173 or a history of drug induced leukopenia/neutrope­ Partners, Inc. nia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Fluphenazine 45849F Decanoate Injection, USP at the first sign of a decline Revised: September 2010 in WBC in the absence of other causative factors. Pi Font Typesmiths Helvetica (BT) Mathmatical Pi (A) 9/3/10–bw–indd4 CrossTech–63784–Proof 1 CrossTech–63784–Proof M01 Form 45849F No. 4500071745–Job APP–P.O. Decanoate–2 Fluphenazine Helvetica (A) Fonts: