INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
MODECATE INJECTION

SCHEDULING STATUS:
S5

PP ZIMBABWE ONLY

PROPRIETARY NAME
(and dosage form):

MODECATE INJECTION

COMPOSITION
25 mg Fluphenazine Decanoate per mL in sesame oil preserved with 1,5% m/v benzyl alcohol.

PHARMACOLOGICAL CLASSIFICATION
Category A 2.6.1 Phenothiazine and derivative.

PHARMACOLOGICAL ACTION
Fluphenazine decanoate is an esterified trifluoromethyl phenothiazine derivative. Its chemical name is 4-(3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl)-1 piperazine. It is an antipsychotic agent with an extended duration of action.
Fluphenazine has activity at all levels of the central nervous system as well as on multiple organ systems. The mechanism whereby its therapeutic action is exerted is unknown, but may be due to competitive antagonism of dopamine, some of its side effects can be ascribed to competitive antagonism of dopamine, and to blockade of alpha-adrenergic receptors or muscarinic receptors. Fluphenazine is extensively metabolised, undergoing "first pass" metabolism by the liver and is excreted in both the urine and faeces. It is highly protein-bound (>90%) in plasma. The serum half life is approximately 7-10 days.
Fluphenazine crosses the blood-brain barrier, crosses the placenta easily and cannot be removed by dialysis.

INDICATIONS
MODECATE is indicated in the management of manifestations of psychotic disorders. It is of particular value in the treatment of chronic schizophrenia. It is not only useful in the hospital milieu, but is useful because of its long duration of action in the long-term maintenance therapy of chronically psychotic patients who are amenable to out-patient therapy.

CONTRA-INDICATIONS
Patients with suspected or established parkinsonism. Phenothiazine compounds should not be used in patients receiving large doses of hypnotics.
In comatose or severely depressed states.
The presence of blood dyscrasia or liver damage precludes the use of phenothiazines.
In patients who have shown hypersensitivity to fluphenazine; cross-sensitivity to phenothiazine derivatives may occur.
Pregnancy and lactation, as safety has not been established.
Safety and efficacy in children have not been established.
Patients exposed to organophosphate insecticides.

WARNINGS
Neuroleptic Malignant Syndrome (Hyperthermia with Extrapyramidal and Autonomic Disturbances; Neuroleptic-induced Hyperpyrexia):
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with fluphenazine decanoate. 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). The management of NMS should include discontinuation of MODECATE and initiation of appropriate medical treatment.
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.

DOSAGE AND DIRECTIONS FOR USE
The usual adequate dosage of fluphenazine decanoate is 25 mg (1 mL) every three to four weeks. If necessary, adjustments in the amount and the dosage interval may be made in accordance with the patient's response.
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. Although in a large series of patients the optimal dose was usually 25 mg (1 mL) every three to four weeks, the amount required ranged from 12,5 to 100 mg (0,5 to 4 mL). The interval between doses ranged from two weeks to five weeks in most instances, but some patients required doses as often as once every three days for the first few injections, while the response to a single dose was found to last six weeks or longer in a few patients on maintenance therapy.
For patients who have had no previous therapy, it is advisable to initiate treatment with an oral antipsychotic agent or a quick-acting parenteral antipsychotic. When optimal response has been established, fluphenazine decanoate should be administered every three to four weeks. In switching over to fluphenazine decanoate, the quick-acting antipsychotic agent should be administered concurrently for 3 days, and then discontinued.
For patients on short-acting phenothiazine drugs, fluphenazine decanoate at 25 mg (1 mL) every three to four weeks should be adequate. The previous antipsychotic agent should be administered concurrently for 3 days, and then discontinued.
Severely agitated patients may be treated initially with a rapid-acting phenothiazine compound - see package insert accompanying that product for complete information. When acute symptoms have subsided, 25 mg (1 mL) of MODECATE (fluphenazine decanoate) may be administered; subsequent dosage may be adjusted as necessary.
In 'poor risk' patients (those with known hypersensitivity to phenothiazines, or with disorders that predispose to undue reactions) therapy should be initiated cautiously with a quick-acting antipsychotic agent. When optimal response has been established, fluphenazine decanoate should be administered at 25 mg every three weeks. In switching over to fluphenazine decanoate, the quick acting antipsychotic agent should be administered concurrently for 3 days, and then discontinued.
MODECATE may be administered intramuscularly or subcutaneously. A dry needle and syringe should be used. Use of a wet needle or syringe may cause the solution to become cloudy.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
The use of Modecate may impair the mental and physical abilities required for driving a car or operating machinery.
Potentiation of the effects of alcohol may occur with the use of Modecate.
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 other phenothiazine derivatives.
Psychotic patients on large doses of phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, it should be remembered that reduced amounts of anaesthetics or central nervous system depressants may be necessary.
The effects of anticholinergics may be potentiated in some patients receiving fluphenazine because of added anticholinergic effects.
Fluphenazine decanoate administration could be hazardous in patients exposed to extreme heat, since it may impair body temperature regulation.
The preparation should be used with caution in patients with a history of convulsive disorders, since grand mal convulsions have been known to occur.
Use with caution in patients with special medical disorders such as mitral insufficiency or other cardiovascular diseases as well as pheochromocytoma.
Fluphenazine decanoate may elevate prolactin levels, which persists during chronic administration.
The possibility of liver damage, pigmentary retinopathy, lenticular and corneal deposits, and development of irreversible dyskinesia should be remembered when patients are on prolonged therapy.
Central Nervous System: The side effects most frequently reported with phenothiazine compounds are extrapyramidal symptoms including pseudo-parkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonus, and hyperreflexia. Most often these extrapyramidal symptoms are reversible; however, they may be persistent (see following text). With any given 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.
Extrapyramidal reactions may be controlled by administration of anticholinergic drugs and by subsequent reduction in dosage.
Other CNS Effects: Occurrences of Neuroleptic Malignant Syndrome (NMS) have been reported in some patients. Leucocytosis, fever, elevated creatinine phosphokinase (CPK), liver function abnormalities and acute renal failure may also occur with NMS.
Persistent Tardive Dyskinesia: Tardive dyskinesia may appear in some patients on long-term therapy or may occur 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. The syndrome is characterised by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g. protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of the extremities. There is no known effective treatment for tardive dyskinesia; antiparkinsonian agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if symptoms appear. Should it be necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked. It has been reported that fine vermicular movement of the tongue may be an early sign of the syndrome and if the medication is stopped at that time, the syndrome may not develop.
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 dosages of fluphenazine far in excess of the recommended amount. Reactivation or aggravation of the psychotic process may be encountered.
Phenothiazine derivatives have been known to cause restlessness, excitement, or bizarre dreams in some patients.
Modecate should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic psychotic illness that 1)is known to respond to neuroleptic medication, and 2)for whom alternative, equally effective but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
Autonomic Nervous System: Hypertension and fluctuations in blood pressure have been reported with fluphenazine decanoate.
Hypotension has rarely presented a problem with fluphenazine, however, patients with phaeochromocytoma, cerebral vascular 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 Modecate is administered. If severe hypotension should occur, supportive measures including the use of intravenous vasopressor drugs should be instituted immediately.
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 Modecate has caused blurred vision, glaucoma, bladder paralysis, faecal impaction, paralytic ileus, tachycardia, or nasal congestion.
Metabolic and Endocrine: Weight change, peripheral oedema, hyponatremia, syndrome of inappropriate antidiuretic hormone secretion, 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 Modecate therapy.
Allergic Reactions: Skin disorders such as itching, erythema, urticaria, seborrhoea, photosensitivity, eczema and even exfoliative dermatitis have been reported with Modecate. The possibility of anaphylactoid reactions occurring in some patients should be borne in mind.
Haemotologic: Routine blood counts are advisable since blood dyscrasias including leucopenia, agranulocytosis, thrombocytopenic or non-thrombocytopenic 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 leucocyte count indicates cellular depression, therapy should be discontinued and other appropriate measures instituted immediately.
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. Sometimes, alterations in liver function tests may occur. Hepatitis has been reported in patients receiving fluphenazine.
Other: Sudden, unexpected and unexplained deaths have been reported in hospitalised psychotic patients receiving phenothiazines. Previous brain damage or seizures may be pre-disposing factors; high doses should be avoided in known seizure patients. Several patients have shown sudden flare-ups of psychotic behaviour pattern reflexes shortly before death. Autopsy findings 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.
The following adverse reactions have also occurred with Modecate: Fever, vomiting,
systemic lupus erythematosus-like syndrome, hypotension severe enough to cause fatal cardiac arrest, altered electrocardiographic and electroencephalographic tracings, altered cerebrospinal fluid proteins, cerebral oedema, asthma, laryngeal oedema, and angioneurotic oedema; with long-term use, skin pigmentation, lenticular and corneal opacities, liver or kidney damage and pigmentary retinopathy.

Interactions with other Medications:
CNS Depressants/Alcohol/Analgesics: The patient's reponse to alcohol and other CNS depressants such as hypnotics, sedatives or strong analgesics, may be exaggerated while taking Modecate. Combined use with narcotic analgesics may cause hypotension as well as CNS or respiratory depression.
Tricyclic Antidepressants: Modecate impairs the metabolism of tricyclic antidepressants. Serumconcentrations of both the tricyclic and Modecate are increased. Sedative and antimuscarinic effects may be potentiated or prolonged. Tricyclics may increase the potential for arrhythmia.
Lithium: Neurotoxicity has been reported rarely when lithium is used concomitantly with Modecate.
ACE-inhibitors/Thiazide Diuretics: Hypotension may result via additive or synergistic pharmacological activity.
Antihypertensives: The antihypertensive action of guanethidine, clonidine and possibly other adrenergic-blocking antihypertensive agents may be blocked. Clonidine may decrease the antipsychotic activity of Modecate.
Beta Blockers: Plasma levels of both drugs may be increased. Dosage reduction of both drugs is recommended.
Adrenaline and other sympathomimetics: Modecate may antagonize the action of adrenaline and other sympathomimetics and may cause severe hypotension.
Levodopa: Modecate may impair the anti-Parkinson effect of L-Dopa.
Anticholinergics/Antimuscarinics: Anticholinergic effects may be exaggerated when Modecate is administered with anticholinergic agents, especially in older patients. Antimuscarinic effects may be potentiated or prolonged. Close supervision and careful dosage adjustment are required when Modecate is used with other anticholinergic or antimuscarinic drugs.
Anticonvulsants: Modecate may increase or decrease the levels of phenytoin.
Anticoagulants: Modecate may alter the effects of anticoagulants.
Antidiabetics: Modecate has been associated with loss of blood glucose control in patients with diabetics.
Cimetidine: Cimetidine may reduce plasma concentrations of Modecate.
Amphetamine/Anorectic Agents: Concurrent administration may produce antagonistic pharmacological effects.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Overdosage should be treated symptomatically and supportively. Extrapyramidal reactions will respond to oral or parenteral antiparkinsonian drugs such as procyclidine or benztropine. In cases of severe hypotension all procedures for the management of circulatory shock should be instituted, e.g. vasoconstrictors and/or intravenous fluids. Sedation may also be a symptom. CNS depression may progress to coma. Restlessness, confusion and excitement may occur with early or mild intoxication.
In general, phenothiazines do not produce psychic dependence, however, gastritis, nausea and vomiting, dizziness, and tremulousness have been reported following abrupt cessation of high dose therapy. Reports suggest that these symptoms can be reduced if concomitant antiparkinsonian agents are continued for several weeks after the phenothiazine is withdrawn.
Facilities should be available for periodic checking of hepatic function, renal function and the blood picture. Renal function of patients on long-term therapy should be monitored; if the blood urea nitrogen becomes abnormal, treatment should be discontinued.
As with any phenothiazine, the physician should be alert to the possible development of 'silent pneumonias' in patients under treatment with fluphenazine decanoate.

1.	Hypothermia should be conservatively treated by monitoring unless the temperature is below 30°C.
2.	Where the patient is vulnerable and at risk for infection, especially pneumonia, antibiotics should be instituted.
3.	Hypotension may occur as well and is controlled by IV noradrenalin. Usual pressor amines, including adrenalin, should not be given.
4.	Extrapyramidal tract symptoms will resolve on withholding the medication but can be controlled by IV benztropine mesylate 1 to 2 mg, diphenhydramine hydrochloride 20 to 30 mg or procyclidine hydrochloride 10 mg. Barbiturates may be effective if these fail.

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

IDENTIFICATION
1 mL glass ampoules or 10 mL amber multidose vials containing a pale yellow viscous fluid.

PRESENTATION
1 mL ampoules and 10 mL vials.

STORAGE INSTRUCTIONS
Store at room temperature not exceeding 25°C. Avoid excessive heat. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
C/2.6.1/35

NAME AND BUSINESS ADDRESS OF APPLICANT
BRISTOL-MYERS SQUIBB (PTY) LTD*
47 Van Buuren Road
BEDFORDVIEW, 2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT
17 March 2000

*Authorised User of the TM MODECATE

Updated on this site: June 2005
Source: Pharmaceutical Industry
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