Modecate Concentrate 100 mg/mL

Information for the Patient

Modecate Concentrate

Pharmacology

Pharmacokinetics

Indications

Pediatrics (<18 years of age)

Geriatrics (≥65 years of age)

Adults

Precautions

Amphetamine/Anorectic Agents

Drug Interactions

Blood Dyscrasias, Liver Damage

Elevated Prolactin Levels

Antiparkinsonian Medications

Lithium

Convulsions

Antidiabetics

Autonomic Nervous System Effects, including Blood Pressure Changes and Paralytic Ileus

Abrupt Withdrawal

Anticoagulants

Anticonvulsants

Silent Pneumonia

Geriatrics

Antacids/Antidiarrheal Agents

Epinephrine and Other Sympathomimetics

Medicines that Prolong the QT Interval

Beta Blockers

Allergic Cross-Sensitivity

Anticholinergics/Antimuscarinics

ACE inhibitors/Thiazide Diuretics

Tricyclic Antidepressants

Metrizamide

Antihypertensives

Information to Be Provided to the Patient

Cimetidine

CNS Depressants/Alcohol/Analgesics

Supplied

Each mL of injectable solution contains: fluphenazine decanoate 100 mg. Nonmedicinal ingredients: benzyl alcohol 1.5% w/v (preservative) and sesame oil. Ampuls of 1 mL. Store at room temperature and protect from light. Avoid freezing and extreme heat.

Contraindications

MODECATE (fluphenazine decanoate) is contraindicated in:

• Patients with a history of hypersensitivity to the active or inactive ingredients.

  
  

• Patients, who have shown hypersensitivity to other phenothiazines, including fluphenazine, should not be given fluphenazine decanoate as cross-sensitivity reactions may occur.

  
  

• Patients with marked cerebral atherosclerosis, suspected or established subcortical brain damage, with or without hypothalamic damage, since a hyperthermic reaction with temperatures above 40°C may occur, sometimes not until 14-16 hours after drug administration.

  
  

• Patients with renal insufficiency, pheochromocytoma, or in patients with severe cardiovascular disorders.

  
  

• Patients who are comatose.

  
  

• Patients with severe CNS depression.

  
  

• Patients receiving large doses of CNS depressant medications (e.g., alcohol, barbiturates, narcotics, hypnotics, etc).

  
  

• Patients with blood dyscrasias.

  
  

• Patients with liver damage.

  Warnings

  Tardive Dyskinesia

  Tardive dyskinesia (TD) is a syndrome of involuntary hyperkinetic abnormal movements that occur in predisposed individuals during or following the cessation of long-term neuroleptic drug therapy including fluphenazine. TD is characterized by involuntary, repetitive, purposeless hyperkinetic movements that involve the tongue, face, mouth, lips or jaw, trunk and extremities. The prevalence of TD greatly varies; when the mildest symptoms are included, prevalence can be 70%, whereas severe symptom rates are around 2.5%. The frequency and severity of TD increases with age, particularly in females.

  
  

  The mechanism of TD is not known; though dopamine dysfunction is believed to underlie TD, it may be necessary but not sufficient to explain this complex disorder. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

  
  

  There is no known treatment for established cases of TD, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. However, neuroleptic treatment itself suppresses the signs and symptoms of the syndrome thereby masking the underlying disease process.

  
  

  Given these considerations, neuroleptic drugs should be prescribed in a manner that is most likely to minimize the occurrence of TD. Reducing the dose to the lowest effective level or discontinuing the drug for as long as possible continues to be the most rational approach. In patients who require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

  
  

  If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

  Children

  The safety and efficacy of fluphenazine decanoate in children have not been established. Therefore, fluphenazine decanoate is not indicated for use in the pediatric age group (see Indications).

  Pregnancy

  The safety of use in pregnant women has not been established. Therefore, MODECATE CONCENTRATE (fluphenazine decanoate) should not be administered to women of childbearing potential, particularly during the first trimester of pregnancy, unless, in the opinion of the physician, the expected benefit to the patient outweighs the potential risk to the fetus.

  Neuroleptic Malignant Syndrome (Hyperthermia with Extrapyramidal and Autonomic Disturbances; Neuroleptic-Induced Hyperpyrexia)

  Neuroleptic malignant syndrome is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs.

  
  

  Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

  
  

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

  
  

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

  
  

  If a patient requires antipsychotic drug treatment after recovery from NMS, the potential re-introduction of therapy should be very carefully considered. The patient should be carefully monitored, since recurrence of NMS has been reported.

  Occupational Hazards

  The use of this drug may impair the mental and physical abilities required for driving a car or operating heavy machinery particularly during the first days of therapy. Potentiation of the effects of alcohol may also occur.

  Other Warnings

  The use of this drug may impair the mental and physical abilities required for driving or operating heavy machinery, particularly during the first days of therapy. Potentiation of the effects of alcohol may occur with the use of this drug (see Precautions, Information to Be Provided to the Patient).

  Prolongation of the QT Interval

  As with other neuroleptics, very rare cases of QT interval prolongation have been reported with MODECATE. Neuroleptic phenothiazines may potentiate QT interval prolongation, which increases the risk of onset of serious ventricular arrhythmias of the torsades de pointes type, which is potentially fatal (sudden death). QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalemia, and congenital or acquired (i.e., drug induced) QT prolongation (see also Adverse Events, Prolongation of the QT Interval). As well, concomitant treatment with other drugs known to cause QT prolongation should be avoided (for more information, see Drug Interactions, Medicines that Prolong the QT Interval).

  Cerebrovascular Events, Including Stroke, in Elderly Patients with Dementia

  Elderly patients with dementia treated with certain atypical antipsychotic drugs are at an increased risk of Cerebrovascular Adverse Events (CVAEs) such as stroke and transient ischemic attacks, as well as death, compared to placebo. The mechanism of this increased risk is not known. As an increase in the risk with other antipsychotic drugs cannot be excluded, fluphenazine should be used with caution in the elderly with dementia.

  
  
  

  Adverse Effects

  Hematologic

  Leukopenia, agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura, eosinophilia, and pancytopenia have been observed with phenothiazine derivatives. If any soreness of the mouth, gums or throat or any symptoms of upper respiratory infection occur and confirmatory leukocyte count indicates cellular depression, therapy should be discontinued and other appropriate measures instituted immediately.

  Central Nervous System

  Extrapyramidal Symptoms: The adverse effects most frequently reported with phenothiazine compounds are extrapyramidal symptoms including pseudoparkinsonism (tremor, rigidity, etc.), dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyperreflexia. Most often these extrapyramidal symptoms are reversible; however, they may be persistent. With any given phenothiazine derivative, the incidence and severity of such events depend more on individual patient sensitivity than on other factors, but dosage level and patient age are also determinants.

  
  

  MODECATE CONCENTRATE (fluphenazine decanoate) produces a higher incidence of extrapyramidal reactions than the less potent piperazine derivatives or the straight-chain phenothiazines such as chlorpromazine. Extrapyramidal reactions tend to occur in the first few days after an injection of fluphenazine decanoate. Caution should be exercised in those who have marked extrapyramidal reactions to oral phenothiazines or similar drugs, particularly elderly females. Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These symptoms can usually be controlled by administration of anticholinergic or antiparkinson drugs (such as benztropine mesylate) and by subsequent reduction in dosage.

  
  

  The use of prophylactic antiparkinson medication may be considered, although its therapeutic value has not yet been established.

  
  

  Tardive Dyskinesia: (see Warnings, Tardive Dyskinesia). The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth, or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). These may be accompanied by involuntary movements of the trunk and the extremities. The severity of the syndrome and the degree of impairment produced vary widely.

  
  

  As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may occur upon dosage reduction or after drug therapy has been discontinued. The risk seems to be greater in elderly patients on high dose therapy, especially females. The symptoms are persistent and in some patients appear to be irreversible.

  
  

  There is no known effective treatment for tardive dyskinesia; antiparkinsonian agents usually do not alleviate the symptoms of this syndrome.

  
  

  Neuroleptic drugs should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Reducing the dose to the lowest effective level or discontinuing the drug for as long as possible continues to be the most rational approach. In patients who require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

  Cerebrovascular Stroke-like Events

  An approximately 3-fold increased risk, compared to placebo, of cerebrovascular adverse events, such as stroke and transient ischemic attacks as well as death, has been seen in randomized, placebo-controlled clinical trials, in the dementia population with some atypical antipsychotics. Fluphenazine should be used with caution in the elderly with dementia. (See Warnings, Cerebrovascular Events, Including Stroke, in Elderly Patients with Dementia.)

  Autonomic Nervous System

  (See also Warnings.) Hypotension, hypertension and fluctuations in blood pressure have been reported with fluphenazine.

  
  

  Patients with pheochromocytoma, cerebral vascular or renal insufficiency, or a severe cardiac reserve deficiency such as mitral insufficiency, appear to be particularly prone to hypotensive reactions with phenothiazine compounds and should therefore be observed closely when the drug is administered.

  
  

  Autonomic reactions including nausea and loss of appetite, salivation, polyuria, perspiration, dry mouth, headache, and constipation may occur. Autonomic effects can usually be controlled by reducing or temporarily discontinuing dosage.

  
  

  In some patients, phenothiazine derivatives have caused blurred vision, glaucoma, bladder paralysis, fecal impaction, paralytic ileus, tachycardia, or nasal congestion.

  Metabolic and Endocrine

  Weight change, peripheral edema, hyponatremia, syndrome of inappropriate antidiuretic hormone secretion, abnormal lactation, gynecomastia, menstrual irregularities, false pregnancy test results, impotency in men and libido changes in women have all been known to occur in some patients on phenothiazine therapy.

  Others

  Sudden, unexpected and unexplained deaths have been reported in hospitalized psychotic patients receiving phenothiazines. Previous brain damage or seizures may be predisposing factors; high doses should be avoided in known seizure patients. Several patients have shown flare-ups of psychotic behaviour patterns shortly before death. Autopsy findings have usually revealed acute fulminating pneumonia or pneumonitis, aspiration of gastric contents or intramyocardial lesions.

  
  

  Potentiation of central nervous system depressants (opiates, analgesics, antihistamines, barbiturates, alcohol) may occur (see Contraindications).

  
  

  The following adverse reactions have also occurred with phenothiazine derivatives: fever, vomiting, systemic lupus erythematosus like syndrome, hypotension severe enough to cause fatal cardiac arrest, altered ECG and EEG tracings, altered CSF proteins, cerebral edema, asthma, disturbances of body temperature (hypo- or hyperthermia), laryngeal edema, and angioneurotic edema. Skin pigmentation, and lenticular and corneal opacities have been seen with long-term use.

  
  

  Injections of fluphenazine decanoate are well tolerated, local tissue reactions occur only rarely.

  Other CNS Effects

  Drowsiness or lethargy, if they occur, may necessitate a reduction in dosage; the induction of a catatonic-like state has been known to occur with high dosages of fluphenazine. As with other phenothiazine compounds, reactivation or aggravation of psychotic processes may be encountered. In some patients, phenothiazine derivatives have been known to cause restlessness, excitement, or bizarre dreams.

  
  

  Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported in patients on neuroleptic therapy. The syndrome is characterized by hyperthermia, muscular rigidity, autonomic instability (labile blood pressure, tachycardia, diaphoresis), akinesia, and altered consciousness, sometimes progressing to stupor or coma. Leukocytosis, fever, elevated CPK, liver function abnormalities, and acute renal failure may also occur with NMS. Neuroleptic therapy should be discontinued immediately and vigorous symptomatic treatment implemented since the syndrome is potentially fatal (see Warnings, Neuroleptic Malignant Syndrome (Hyperthermia with Extrapyramidal and Autonomic Disturbances; Neuroleptic-Induced Hyperpyrexia).

  Prolongation of the QT Interval

  QT prolongation, ventricular arrhythmias, ventricular fibrillation, ventricular tachycardia, cardiac arrest, torsades de pointes and sudden unexplained death are class effects of phenothiazines. (See Warnings, Prolongation of the QT Interval, and Precautions, Drug Interactions.)

  Allergic Reactions

  Skin disorders such as itching, erythema, urticaria, seborrhea, photosensitivity, eczema and exfoliative dermatitis have been reported with phenothiazine derivatives. The possibility of anaphylactoid reactions should be borne in mind.

  Hepatic

  Liver damage as manifested by cholestatic jaundice may be encountered, particularly during the first months of therapy; treatment should be discontinued if this occurs. An increase in cephalin flocculation, sometimes accompanied by alterations in other liver function tests and hepatitis, has been reported in patients receiving the enanthate ester of fluphenazine (a closely related compound).

  
  
  

  Overdose

  Symptoms

  Symptoms of overdose will likely be manifested as severe extrapyramidal reactions, hypotension or sedation. CNS depression may progress to coma with areflexia. Restlessness, confusion and excitement may occur with early or mild intoxication.

  Treatment

  The drug should be withdrawn and the symptoms of overdose treated supportively. Initial hospitalization may be required in cases of large overdose and close medical supervision should be maintained throughout the duration of drug action. Up to several hours after an oral overdose, gastric lavage should be attempted, followed by activated charcoal and then cathartics.

  
  

  An airway should be maintained. If severe hypotension should occur, supportive measures including the use of intravenous vasopressor drugs should be instituted immediately. Levarterenol bitartrate Injection, U.S.P. is the most suitable drug for this purpose; epinephrine should not be used since phenothiazine derivatives have been found to reverse its action, resulting in a further lowering of blood pressure.

  
  

  Extrapyramidal symptoms may be treated with antiparkinsonian agents, and should be continued for several weeks. Antiparkinson medication should be withdrawn gradually to avoid the emergence of rebound extrapyramidal symptoms.

  
  

  Limited experience indicates that phenothiazines are not dialyzable. Hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis are ineffective in phenothiazine poisoning.

  
  
  

  Dosage

  Geriatrics

  The suggested initial test dose is 2.5 mg, gradually adjusted according to the response of the patient. Maintenance doses in the lower range (¼ to ⅓ of those in younger adults) may be sufficient for most elderly patients.

  “Poor Risk” Patients

  MODECATE is contraindicated in patients with known hypersensitivity to phenothiazines (see Contraindications). For patients with disorders that predispose to undue reactions (see Warnings and Precautions), therapy may be initiated cautiously with oral or parenteral fluphenazine hydrochloride. When the pharmacologic effects and an appropriate dosage are apparent, an equivalent dose of MODECATE may be administered. Subsequent dosage adjustments are made in accordance with the response of the patient.

  Adults

  The initial recommended dose is 2.5 mg to 12.5 mg. An initial dose of 12.5 mg is usually well tolerated.

  
  

  The onset of action generally appears between 24 to 72 hours after injection, and the effects of the drug on psychotic symptoms become significant within 48 to 96 hours.

  
  

  Discontinuation of oral neuroleptic medication has been recommended for up to 1 week prior to initiation of depot fluphenazine therapy.

  
  

  Subsequent doses and frequency of administration must be determined for each patient. There is no reliable dosage comparability between a short-acting neuroleptic and depot fluphenazine and, therefore, the dosage of the long-acting drug must be individualized. Except in particularly sensitive patients, a second dose of 12.5 mg or 25 mg can be given 4 to 10 days after the initial injection. Subsequent dosage adjustments are made in accordance with the clinical circumstances and the response of the patient. Patients can usually be controlled with 25 mg or less, every 2 to 3 weeks. Although doses greater than 50 mg are usually not deemed necessary, doses up to 100 mg have been used in some patients. If doses greater than 50 mg are necessary, the next dose and succeeding doses should be increased in increments of 12.5 mg. While the response to a single injection lasts usually 2 to 3 weeks, it may last for 4 weeks or more.

  
  

  After an appropriate dosage adjustment is achieved, regular and continuous supervision and reassessment is considered essential in order to permit any further dosage adjustments that might be required to ensure use of the lowest effective individual dose and avoid troublesome side effects.

  
  

  Since higher doses increase the incidence of extrapyramidal reactions and other adverse effects, the amount of drug used should not be increased in order to prolong the intervals between injections. With higher doses, there is also more variability in the action of depot fluphenazine.

  
  

  MODECATE CONCENTRATE (100 mg/mL) may be administered in patients who complain of discomfort with a large injection volume or when a smaller injection volume is desirable.