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Fluphenazine Decanoate Oily Injection is available as a 25 milligrams/mL solution and as a 100 milligrams/mL solution in sesame oil containing benzyl alcohol 1.5% w/v. It is available in ampoules in the following presentations for intramuscular injection:
Fluphenazine deconoate is an esterified trifluoromethyl phenothiazine derivative. Chemically, fluphenazine is 4-(3-[2-(Trifluoromethyl) phenothiazin-10-y1]propyl)-1 piperazine. It is a highly potent antipsychotic agent with a markedly extended duration of action, available for intramuscular administration.
The basic effects of fluphenazine decanoate appear to be no different from those of fluphenazine hydrochloride. The only exception to this is a prolonged duration of action. The esterification of fluphenazine with decanoic acid markedly prolongs the drug's duration of effect without reducing its activity.
Like all phenothiazine derivatives, fluphenazine decanoate appears to act on the hypothalamus, depressing various components of the mesodiencephalic activating system which is involved in the control of basal metabolism and body temperature, wakefulness, vasomotor tone, emesis, and hormonal balance. In addition, the phenothiazines exert a peripheral autonomic affect to varying degrees. However, the site and mode of action of the phenothiazines have not been completely elucidated.
Fluphenazine and its ester derivatives differ from other phenothiazines in several respects; fluphenazine and its esters are more potent on a milligram basis, appear to be less sedating, and have less potentiating effect on central nervous system depressants and anaesthetics than do some of the other phenothiazine derivatives; they are less likely than some of the older phenothiazines to produce hypotension nevertheless, appropriate cautions should be observed. (See Precautions under Warnings and Precautions, and Adverse Effects).
A long-acting parenteral antipsychotic agent is an invaluable aid both to psychotic patients and to those who are responsible for them. Fluphenazine decanoate reduces hallucinations, delusions, confusion, withdrawal and, to a lesser degree, hostility and agitation. In general, the psychotic patient becomes more co-operative, less withdrawn, more responsive to social situations, and more receptive to psychotherapy or other non-chemotherapeutic measures. In the hospital, the nursing staff is relieved of the need for daily or even more frequent administration of drugs to a class of patients who may be difficult to treat and who frequently dispose of oral medication without swallowing it. In out-patient care, where constant supervision is rarely feasible, the longer interval between injections reduces the problem providing adequate maintenance dosage for patients who often fail to continue daily oral medication and consequently suffer frequent severe recurrences of acute psychotic episodes. Because maintenance medication can be more easily assured through the use of fluphenazine decanoate, it may be possible to release an increasing number of patients from custodial hospital care to an out-patient status.
Fluphenazine decanoate produces far fewer extrapyramidal side effects and a larger proportion of milder extrapyramidal side effects than any other fluphenazine product. A study conducted to determine the effects of fluphenazine decanoate revealed that out of 501 patients, 314 (62.7%) did not exhibit any extrapyramidal side effects. Out of the 187 patients who did show a variety of extrapyramidal side effects, 94 (50%) exhibited symptoms of only mild severity.
Interpatient variations in pharmacokinetics and in dose-response relationships may be influenced by age and genetics as well as by interaction with other agents.
Fluphenazine is extensively metabolized, undergoing "first pass" metabolism by the liver, and is excreted in both the urine and faeces. The degree of antipsychotic activity of the metabolites is still unknown. Fluphenazine is highly protein-bound (greater than 90%) in plasma. Esterification of fluphenazine with a long-chain fatty acid and dissolving it in a sesame seed oil vehicle delays diffusion and availability of free drug released from the oily depot site. Peak plasma concentration occurs within the first 24-hours after intramuscular injection of fluphenazine decanoate.
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. The therapeutic activity then continues for 1 to 4 weeks or longer with average duration of effect of between 3 to 4 weeks. The serum half-life is approximately 7-10 days.
Fluphenazine decanoate is indicated in the long-term management of psychotic disorders including schizophrenia, mania and organic brain syndrome. It is of particular value in the treatment of chronic schizophrenia and for patients who are unreliable at taking oral medication. The drug often alleviates such target symptoms as hallucinations, delusions, confusion and withdrawal. It is not only useful in the hospital milieu but is unparalleled, because of its long duration of action in the long-term maintenance therapy of chronically psychotic patients who are amenable to out-patient therapy.
Fluphenazine decanoate has not been shown to be effective in the management of behavioural complications in patients with mental retardation.
Fluphenazine Decanoate Oily Injection should be administered under the supervision of only those who are experienced in the clinical use of neuroleptic agents. The optimal amount of fluphenazine decanoate and the frequency of administration must be determined for each patient, since dosage requirements have been found to vary with clinical circumstances as well as with individual response to the drug. The response to Fluphenazine Decanoate Oily Injection may be delayed (see below) and if the medication is withdrawn it may take several weeks for symptoms to become apparent.
Fluphenazine decanoate injections are given intramuscularly. A dry syringe and needle of at least 21 gauge should be used. Use of a wet needle or syringe may cause solution to become cloudy.
To begin therapy with Fluphenazine Decanoate Oily Injection the following regimens are suggested:
For most patients, a dose of 12.5 to 25mg may be given to initiate therapy. The onset of action generally appears between 24 and 72 hours after injection and the effects of the drug on psychotic symptoms becomes significant within 48 to 96 hours. Subsequent injections and the dosage interval are determined in accordance with the patient's response. When administered as a maintenance therapy, a single injection may be effective in controlling schizophrenic symptoms up to four weeks or longer. The response to a single dose has been found to last as long as six weeks in a few patients on maintenance therapy. It may be advisable that patients who have no history of taking phenothiazines should be treated initially with a shorter-acting form of fluphenazine (Anatensol) before administering the decanoate to determine the patient's response to fluphenazine and to establish appropriate dosage. For psychotic patients who have been stabilised on a fixed daily dosage of fluphenazine hydrochloride tablets or fluphenazine hydrochloride elixir, conversion of therapy from these short-acting oral forms to the long-acting injectable fluphenazine decanoate may be indicated.
Appropriate dosage of fluphenazine decanoate should be individualised for each patient and responses carefully monitored. No precise formula can be given to convert to use of fluphenazine decanoate; however, a controlled multicentered study in patients receiving oral doses from 5 to 60mg fluphenazine hydrochloride daily, showed that 20 mg fluphenazine hydrochloride daily was equivalent to 25mg fluphenazine decanoate every three weeks. This represents an approximate conversion ratio of 12.5mg of fluphenazine decanoate every three weeks for every 10mg of fluphenazine hydrochloride daily.
Once conversion to fluphenazine decanoate is made, careful clinical monitoring of the patient and appropriate dosage adjustment should be made at the time of each injection.
Severely agitated patients may be treated with a rapid-acting phenothiazine compound such as Anatensol. When acute symptoms have subsided, 25mg of Fluphenazine Decanoate Oily Injection may be administered; subsequent dosage is adjusted as necessary.
'Poor risk' patients (those with known hypersensitivity to phenothiazines, or with disorders that predispose to undue reactions): Therapy may be initiated cautiously with oral fluphenazine hydrochloride. When the pharmacological effects and an appropriate dosage are apparent, an equivalent dose of fluphenazine decanoate may be administered. Subsequent dosage adjustments are made in accordance with the response of the patient.
The optimal amount of the drug and the frequency of administration must be determined for each patient, since dosage requirements have been found to vary with clinical circumstances as well as with individual response to the drug.
Dosage should not exceed 100mg. If doses greater than 50mg are deemed necessary, the next dose and succeeding doses should be increased cautiously in increments of 12.5mg.
Antipsychotic medication should be used with care in elderly patients (>60 years old), as these patients have a greater potential for adverse effects.
Doses in the lower range (1/4 to 1/3 of those in younger adults) should be sufficient for most elderly patients. Response should be monitored and dose adjusted. If an increase is necessary, doses should be gradually increased.
Fluphenazine Decanoate Oily Injection is contraindicated in patients with marked cerebral atherosclerosis, suspected or established subcortical brain damage, blood dyscrasias, phaeochromocytoma, severe cardiac insufficiency or renal or liver damage. Fluphenazine Decanoate Oily Injection is further contraindicated in comatosed patients, those in severely depressed states or patients receiving large doses of CNS depressants (alcohol, barbiturates, narcotics, hypnotics etc). It is not recommended for the treatment of anxiety and tension states or geriatric confusion and agitation.
Fluphenazine Decanoate Oily Injection is contraindicated in patients who have shown hypersensitivity to the active and inactive ingredients. Caution should be observed in patients with a history of sensitivity to other phenothiazines, as cross-sensitivity may occur.
Fluphenazine decanoate is not intended for use in children under 12 years of age.
The use of Fluphenazine Decanoate Oily Injection may impair the mental and physical abilities required for driving a car or operating heavy machinery. Potentiation of the effects of alcohol may occur with the use of this medication.
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with neuroleptic (antipsychotic) drugs, including fluphenazine. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. 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.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic agents. 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 dysrhythmias).
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
The safety for the use of fluphenazine decanoate during pregnancy has not yet been established; therefore the possible hazards should be weighed against the potential benefits when administering this drug to pregnant patients.
Because of the possibility of cross-sensitivity, fluphenazine decanoate should be used cautiously in patients who have developed cholestatic jaundice, dermatoses or other allergic reactions to phenothiazine derivatives.
Liver damage, rarely manifested by cholestatic jaundice, may be encountered during therapy. Treatment should be discontinued if this occurs. Alteration in cephalin flocculation or alkaline phosphatase and/or increased thymol turbidity (without or with leucocytosis), sometimes accompanied by abnormalities in other liver function tests, have been reported in patients receiving fluphenazine decanoate who have had no clinical evidence of liver damage. This, however is not uncommon with phenothiazine therapy.
Renal function of patients on long-term therapy should be monitored; if BUN (blood urea nitrogen) becomes abnormal, treatment should be discontinued.
Routine blood counts are advisable on long-term therapy since rare instances of blood dyscrasias including leucopenia, agranulocytosis, thrombocytopenic or non-thrombocytopenia purpura, eosinophilia, and pancytopenia have been reported with phenothiazine derivatives. If any soreness of the mouth, gums or throat, or any symptoms of upper respiratory infection occur and a leucocyte count confirms cellular depression; therapy should be discontinued and appropriate measures instituted immediately.
Fluphenazine Decanoate Oily Injection should be used with caution in patients exposed to extreme heat or phosphorus insecticides; in patients with epilepsy, a history of convulsive disorders or conditions predisposing to epilepsy, (since grand mal seizures have been known to occur); in patients with special medical disorders such as mitral insufficiency, cardiac arrhythmias or other cardiovascular diseases; in patients with severe respiratory disease or thyrotoxicosis and in patients who have exhibited idiosyncrasy to other centrally-acting drugs.
When undergoing surgery, psychotic patients on large doses of phenothiazine preparation should be watched carefully for possible hypotensive phenomena. Moreover, it should be remembered that a reduction in dosage of anaesthetic or central nervous system depressants may be required.
The effect of atropine may be potentiated in some patients because of added anticholinergic effects of fluphenazine.
As with any phenothiazine, the physician should be alert to the possible development of 'silent pneumonias' in patients under treatment with fluphenazine decanoate.
Fluphenazine decanoate should be administered under the direction of a physician experienced in the clinical use of psychotropic drugs, particularly phenothiazine derivatives. Furthermore, facilities should be available for periodic checking of the patient's hepatic function, renal function and haematological status.
Caution should be exercised in those who have marked extrapyramidal reactions to oral phenothiazines or similar drugs, particularly elderly females. Such patients should start on half the normal dose.
Neuroleptic medication elevates prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in-vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.
Fluphenazine Decanoate Oily Injection may be likely to produce minor or moderate adverse effects that may impair the patient's ability to concentrate and react and therefore constitute a risk in the ability to drive and use machines.
Phenothiazines increases prolactin levels, which may affect human breast cancers, one-third of which are prolactin dependent in vitro. Although clinical studies have not shown a clear association between chronic administration of antipsychotic drugs and an increase in the incidence of breast cancers, it may be a factor of importance when prescribing fluphenazine for patients in which breast cancer was previously detected.
Chromosomal aberrations in spermatocytes and abnormal sperm have been demonstrated in rodents treated with certain neuroleptic drugs.
The effect of phenothiazines on human fertility is not known; however, phenothiazines have been found to depress spermatogenesis in animals at doses greatly exceeding the human dose.
The side effects more frequently reported with phenothiazine compounds and other antipsychotic agents are extrapyramidal symptoms such as pseudo-parkinsonism (tremor, rigidity, etc), akathisia, dystonia, dyskinesia, oculogyric crisis, and opisthotonos etc. They are; usually reversible however, a persistent pseudo-parkinsonian syndrome may develop after prolonged administration of phenothiazines. Extrapyramidal reactions may be alarming, and the patient should be forewarned and reassured. These reactions can usually be controlled by administration of anti-parkinsonism drugs (such as benztropine mesylate) and if necessary, reduction in dosage.
This syndrome is characterised by rhythmic, stereo-typed, dyskinetic, involuntary movements (particularly of the face, mouth, tongue and jaw) which resemble the facial grimaces of encephalitis. These may be accompanied by choreiform movements of the limbs. In these chronic cases, the symptoms may persist after drug withdrawal and appear to be irreversible in some patients. Anti-parkinsonian agents may not be of benefit in these instances. The risk of developing this persistent syndrome appears to be greatest in elderly female patients with organic brain disease or damage, who have been receiving fairly large doses of phenothiazines for a prolonged period. To increase the likelihood of detecting the syndrome at the earliest possible time, the dosage of neuroleptic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. This manoeuvre is critical, since neuroleptic drugs may mask the signs of the syndrome.
Occurrences of neuroleptic malignant syndrome (NMS) have been reported in patients on neuroleptic therapy. Leukocytosis, elevated CPK, liver function abnormalities, and acute renal failure may also occur with NMS.
A reduction in dosage or symptomatic treatment may be necessary to relieve drowsiness, lethargy, or depression, if they occur. Impairment of judgement and mental skills and epileptiform attacks are occasionally seen. As with other phenothiazines, reactivation or aggravation of psychotic processes may be encountered. Phenothiazine derivatives have been known to cause restlessness, excitement, or bizarre dreams in some patients. Alterations in electroencephalographic tracings or cerebrospinal fluid proteins may occur; cerebral oedema may rarely occur.
Hypotension has rarely presented a problem with fluphenazines. However, patients with phaeochromocytoma, cerebral vascular or renal insufficiency, or a severe cardiac reserve deficiency such as may occur in mitral insufficiency, appear to be particularly prone to hypotensive reactions with phenothiazines; they should therefore be observed closely when the drug is administered. If severe hypotension should occur, supportive measures including the use of intravenous vasopressor drugs should be instituted immediately. Noradrenaline tartrate is the most suitable agent for this purpose; adrenaline should not be used since phenothiazine derivatives have been found to reverse its action, further lowering of blood pressure (that is, neuroleptics block peripheral alpha adrenergic receptors thus inhibiting the alpha vasoconstricting effects of adrenaline and leaving the beta-vasodilator effect relatively unopposed).
Hypertension and fluctuations in blood pressure have been reported with phenothiazines.
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, faecal impaction, paralytic ileus, tachycardia or nasal congestion.
Weight change, peripheral oedema, abnormal lactation, gynaecomastia, menstrual irregularities, false results on pregnancy tests, impotency in men, and increased libido in women have all been known to occur in some patients on phenothiazine therapy.
Skin disorders such as itching, erythema, urticaria, seborrhoea, photosensitivity, eczema and even exfoliative dermatitis have been reported with phenothiazine derivatives. The possibility of anaphylactic reactions occurring in some patients should be borne in mind. Asthma, laryngeal edema, and angioneurotic edema may rarely occur.
Routine blood counts are advisable during therapy since blood dyscrasias including leukopenia, agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura, eosinophilia, and pancytopenia have been observed with phenothiazine derivatives. Furthermore, if any soreness of the mouth, gums or throat, or any symptoms of upper respiratory infection occur and confirmatory leukocyte count indicates bone marrow depression, therapy should be discontinued and other appropriate measures instituted immediately.
Cholestatic jaundice has been encountered with fluphenazine treatment, particularly during the first months of therapy. Treatment should be discontinued if jaundice occurs. Alterations in liver function tests have been reported in patients receiving fluphenazine who have had no clinical evidence of liver damage.
Sudden, unexpected and unexplained deaths have been reported in hospitalised 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 sudden flare-ups of psychotic behaviour patterns shortly before death. Autopsy findings in these cases have usually revealed acute fulminating pneumonia or pneumonitis, aspiration of gastric contents, or intramyocardial lesions.
Although this is not a general feature of fluphenazine, potentiation of central nervous system depressants (opiates, analgesics, antihistamines, barbiturates, alcohol) may occur - See Precautions under Warnings and Precautions for patients undergoing surgery.
The following adverse reactions have also occurred with phenothiazine derivatives; hypotension severe enough to cause fatal cardiac arrest, ECG changes particularly prolongation of the QT interval which may lead to serious arrhythmias, disturbances of body temperature (hypo- and hyperthermic), potentiation of reactions to extreme heat, potentiation of reactions to phosphorus insecticides, asthma, laryngeal oedema, angioneurotic oedema, pigmentary retinopathy, systemic lupus erythematosus-like syndrome; with long-term use, skin pigmentation, and lenticular and corneal opacities have also occurred. Injections of fluphenazine decanoate are extremely well tolerated locally and tissue reactions occur only rarely.
The possibility should be borne in mind that phenothiazines may:
Overdose of fluphenazine may be expected to produce effects that are extensions of common adverse effects. Severe extrapyramidal effects, hypotension and sedation are the principal effects reported. Coma with respiratory depression and hypotension may occur, as can cardiac arrhythmias.
Due to its long duration of action, manifestations of overdose with Fluphenazine Decanoate Oily Injection may be prolonged.
Treatment of fluphenazine overdose is generally supportive. A patent airway should be established by the use of an oropharyngeal airway or endotracheal tube and respiratory depression may need to be managed by artificial respiration. Haemodialysis is of little or no value in the treatment of poisoning.
Intravenous fluid replacement and vasopressor agents, such as metaraminol, noradrenaline (norepinephrine) or dopamine may counteract hypotension and circulatory collapse.
Adrenaline (epinephrine) should not be used.
Anti-Parkinsonian medication should be administered parenterally to control extrapyramidal reactions. ECG and vital signs should be monitored. Seizures may be treated with intravenous diazepam. If seizures are uncontrolled or recur, use intravenous phenobarbitone or phenytoin. Treat arrhythmias with intravenous phenytoin. Body temperature and respiratory function should be maintained.
As another phenothiazine, chlorpromazine may cause severe dermatitis in sensitised persons it is recommended that pharmacists, nurses and others who handle Fluphenazine Decanoate Oily Injection frequently should avoid skin contact with fluphenazine.
Store below 25ºC. Do not refrigerate. Protect from light. Parenteral drug products should be inspected visually for particles and discolouration prior to administration, whenever solution and container permit.
Prescription Medicine.
Fluphenazine Decanoate Oily Injection BP is available in the following strengths and packs:
| Strength | Packs |
|---|---|
| 12.5 mg in 0.5 mL | 5 x 1 mL ampoules |
| 25 mg in 1 mL | 5 x 1 mL ampoules |
| 50 mg in 2 mL | 5 x 2 mL ampoules |
| 100 mg in 1 mL (High Strength) |
5 x 1 mL ampoules |
Fluphenazine decanoate belongs in the phenothiazine class of compounds and has the chemical formula of 2-[4-[3-(2-(trifluoromethyl)phenothiazin-10-yl)propyl]piperazin-1-yl]ethyl decanoate (C32H44F3N3O2S, MW = 591.8, CAS number 5002-47-1). It is a pale yellow viscous liquid or a yellow solid. It is practically insoluble in water; very soluble in dehydrated alcohol, ether and dichloromethane; and freely soluble in methanol.
Hospira NZ Limited
23 Haining Street
Te Aro
Wellington
New Zealand
1 October 2007