MODECATE INJECTION 25MG/ML

SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Modecate Injection 25mg/ml

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ampoule contains 25mg/ml of the active substance Fluphenazine Decanoate.
Also contains sesame oil (q.s.).
Benzyl alcohol 15 mg/ml.
For full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Solution for Injection
Pale yellow clear, oily liquid

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
For the treatment and maintenance of schizophrenic patients and those
with paranoid psychoses.
While Modecate injection has been shown to be effective in acute states, it is
particularly useful in the maintenance treatment of chronic patients who are
unreliable at taking their oral medication, and also of those who do not
absorb their oral phenothiazine adequately.

4.2

Posology and method of administration
Dosage and Administration
Adults
It is recommended that patients be stabilised on the injection in hospital.
Recommended dosage regimes for all indications:
A. Patients without previous exposure to a depot fluphenazine formulation:
Initially 0.5ml i.e. 12.5mg (0.25 ml i.e. 6.25mg for patients over 60) by deep
intramuscular injection into the gluteal region.
The onset of action generally appears between 24 and 72 hours after injection
and the effects of the drug on psychotic symptoms become significant within
48 to 96 hours. Subsequent injections and the dosage interval are determined

in accordance with the patient’s response. When administered as maintenance
therapy, a single injection may be effective in controlling schizophrenic
symptoms for up to four weeks or longer.
It is desirable to maintain as much flexibility in the dose as possible to achieve
the best therapeutic response with the least side-effects; most patients are
successfully maintained within the dose range 0.5ml (12.5mg) to 4.0ml
(100mg) given at a dose interval of 2 to 5 weeks.
Patients previously maintained on oral fluphenazine:
It is not possible to predict the equivalent dose of depot formulation in view of
the wide variability of individual response.
B. Patients previously maintained on depot fluphenazine:
Patients who have suffered a relapse following cessation of depot fluphenazine
therapy may be restarted on the same dose, although the frequency of
injections may need to be increased in the early weeks of treatment until
satisfactory control is obtained.
Elderly:
Elderly patients may be particularly susceptible to extrapyramidal reactions,
sedative and hypotensive effects. In order to avoid this, a reduced maintenance
dosage may be required and a smaller initial dose (see above).
Children:
Not recommended for children.
* Where a smaller volume of injection is desirable, patients may be
transferred directly to the equivalent dose of Modecate Concentrate
injection on the basis that 1ml Modecate Concentrate injection is
equivalent to 4ml Modecate injection.
Note
The dosage should not be increased without close supervision and it should
be noted that there is a variability in individual response.
The response to antipsychotic drug treatment may be delayed. If drugs are
withdrawn, recurrence of symptoms may not become apparent for several
weeks or months.
Route of administration: Intramuscular.

4.3

Contraindications
The product is contraindicated in the following cases:
Comatose states
Marked cerebral atherosclerosis
Phaeochromocytoma
Renal failure
Liver failure
Severe cardiac insufficiency
Severely depressed states

Existing blood dyscrasias
Hypersensitivity to Fluphenazine Decanoate or to any of the excipients
Because of the content of benzyl alcohol Modecate injection must not be given to
newborns or premature neonates.

4.4

Special warnings and precautions for use
Caution should be exercised with the following:
Liver disease
Renal impairment
Cardiac arrhythmias, cardiac disease
Thyrotoxicosis
Severe respiratory disease
Epilepsy, conditions predisposing to epilepsy (e.g. alcohol withdrawal or brain damage)
Parkinson's disease
Patients who have shown hypersensitivity to other phenothiazines
Personal or family history of narrow angle glaucoma
In very hot weather
The elderly, particularly if frail or at risk of hypothermia
Hypothyroidism
Myasthenia gravis
Prostatic hypertrophy

Patients with known or with a family history of cardiovascular disease should
receive ECG screening, and monitoring and correction of electrolyte balance
prior to treatment with fluphenazine.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic
drugs. Since patients treated with antipsychotics often present with acquired risk
factors for VTE, all possible risk factors for VTE should be identified before and
during treatment with fluphenazine and preventative measures undertaken.
Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia
have been described after abrupt cessation of antipsychotic drugs. Recurrence of
psychotic symptoms may also occur, and the emergence of involuntary
movement disorders (such as akathisia, dystonia and dyskinesia) has been
reported. Therefore, gradual withdrawal is advisable.
Psychotic patients on large doses of phenothiazines who are undergoing surgery
should be watched carefully for hypotension. Reduced amounts of anaesthetics
or central nervous system depressants may be necessary.
Fluphenazine should be used with caution in patients exposed to organophosphorus
insecticides
Neuroleptic drugs elevate prolactin levels, and an increase in mammary neoplasms has
been found in rodents after chronic administration. However, studies to date have not
shown an association between chronic administration of these drugs and human
mammary tumours.
As with any phenothiazine, the physician should be alert to the possibility of “silent
pneumonias” in patients receiving long-term fluphenazine.
Increased Mortality in Elderly people with Dementia

Data from two large observational studies showed that elderly people with dementia who
are treated with antipsychotics are at a small increased risk of death compared with those
who are not treated. There are insufficient data to give a firm estimate of the precise
magnitude of the risk and the cause of the increased risk is not known.
Fluphenazine is not licensed for the treatment of dementia-related behavioural
disturbances.
Modecate contains benzyl alcohol as a preservative and must not be given to
premature babies or neonates. The administration of medicines containing benzyl
alcohol as a preservative may cause toxic reactions and anaphylactoid reactions in
children up to 3 years old.
The administration of medications containing benzyl alcohol to newborns or
premature neonates has been associated with fatal ‘Gasping Syndrome’ (symptoms
include a striking onset of gasping syndrome, hypotension, bradycardia, and cardiovascular collapse). As benzyl alcohol may cross the placenta, solution for injection
should be used with caution in pregnancy.

4.5

Interaction with other medicinal products and other forms of interaction
The possibility should be borne in mind that phenothiazines may:
1. Increase the central nervous system depression produced by drugs such as
alcohol, general anaesthetics, hypnotics, sedatives or strong analgesics.
2. Antagonise the action of adrenaline and other sympathomimetic agents and
reverse the blood-pressure lowering effects of adrenergic-blocking agents
such as guanethidine and clonidine.
3. Impair: the anti-parkinsonian effect of L-dopa; the effect of anticonvulsants; metabolism of tricyclic antidepressants; the control of
diabetes.
4. Increase the effect of anticoagulants and antidepressants.
5. Interact with lithium.
Anticholinergic effects may be enhanced by anti-parkinsonian or other
anticholinergic drugs.
Phenothiazines may enhance: the absorption of corticosteroids, digoxin, and
neuromuscular blocking agents.
Fluphenazine is metabolised by P450 2D6 and is itself an inhibitor of this drug
metabolising enzyme. The plasma concentrations and the effects of
fluphenazine may therefore be increased and prolonged by drugs that are
either the substrates or inhibitors of this P450 isoform, possibly resulting in
severe hypotension, cardiac arrhythmias or CNS side effects. Examples of
drugs which are substrates or inhibitors of cytochrome P450 2D6 include antiarrhythmics, certain antidepressants including SSRIs and tricyclics, certain
antipsychotics, β-blockers, protease inhibitors, opiates, cimetidine and ecstasy
(MDMA). This list is not exhaustive.
Concomitant use of barbiturates with phenothiazines may result in reduced
serum levels of both drugs, and an increased response if one of the drugs is
withdrawn.

The effect of fluphenazine on the QT interval is likely to be potentiated by
concurrent use of other drugs that also prolong the QT interval. Therefore,
concurrent use of these drugs and fluphenazine is contraindicated. Examples
include certain anti-arrhythmics, such as those of Class 1A (such as quinidine,
disopyramide and procainamide) and Class III (such as amiodarone and
sotalol), tricyclic antidepressants (such as amitriptyline); certain tetracyclic
antidepressants (such as maprotiline); certain antipsychotic medications (such
as phenothiazines and pimozide); certain antihistamines (such as terfenadine);
lithium, quinine, pentamidine and sparfloxacin. This list is not exhaustive.
Electrolyte imbalance, particularly hypokalaemia, greatly increases the risk of
QT interval prolongation. Therefore, concurrent use of drugs that cause
electrolyte imbalance should be avoided.
Concurrent use of MAO inhibitors may increase sedation, constipation, dry
mouth and hypotension.
Owing to their adrenolytic action, phenothiazines may reduce the pressor
effect of adrenergic vasoconstrictors (i.e. ephedrine, phenylephrine).
Phenylpropanolamine has been reported to interact with phenothiazines and
cause ventricular arrhythmias.
Concurrent use of phenothiazines and ACE inhibitors or angiotensin II
antagonists may result in severe postural hypotension.
Concurrent use of thiazide diuretics may cause hypotension. Diuretic-induced
hypokalaemia may potentiate phenothiazine-induced cardiotoxicity.
Clonidine may decrease the antipsychotic activity of phenothiazines.
Methyldopa increases the risk of extrapyramidal side effects with
phenothiazines.
The hypotensive effect of calcium channel blockers is enhanced by concurrent
use of antipsychotic drugs.
Phenothiazines may predispose to metrizamide-induced seizures.
Concurrent use of phenothiazines and amfetamine/anorectic agents may
produce antagonistic pharmacological effects.
Concurrent use of phenothiazines and cocaine may increase the risk of acute
dystonia.
There have been rare reports of acute Parkinsonism when an SSRI has been
used in combination with a phenothiazine.
Phenothiazines may impair the action of anti-convulsants. Serum levels of
phenytoin may be increased or decreased.
Phenothiazines inhibit glucose uptake into cells, and hence may affect the
interpretation of PET studies using labelled glucose.

4.6

Fertility, pregnancy and lactation
Use in pregnancy: The safety for the use of this drug during pregnancy has not been
established; therefore, the possible hazards should be weighed against the potential
benefits when administering this drug to pregnant patients.
Neonates exposed to antipsychotics (including Modecate) during the third trimester of
pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal
symptoms that may vary in severity and duration following delivery. There have been
reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or
feeding disorder. Consequently, newborns should be monitored carefully.
Nursing mothers: Breast feeding is not recommended during treatment with depot
fluphenazines, owing to the possibility that fluphenazine may be excreted in the breast
milk.

4.7

Effects on ability to drive and use machines
The use of this drug may impair the mental and physical abilities required
for driving a car or operating heavy machinery.

4.8

Undesirable effects
Side Effects: Acute dystonic reactions occur infrequently, as a rule within the first 24-48
hours, although delayed reactions may occur. In susceptible individuals they may occur
after only small doses. These may include such dramatic manifestations as oculogyric
crises and opisthotonos. They are rapidly relieved by intravenous administration of an
anti-parkinsonian agent such as procyclidine.
Parkinsonian-like states may occur particularly between the second and fifth days after
each injection, but often decrease with subsequent injection. These reactions may be
reduced by using smaller doses more frequently, or by the concomitant use of antiparkinsonian drugs such as trihexyphenidyl, benzatropine or procyclidine. Antiparkinsonian drugs should not be prescribed routinely, because of the possible risks of
aggravating anti-cholinergic side effects or precipitating toxic confusional states, or of
impairing therapeutic efficacy.
With careful monitoring of the dose the number of patients requiring anti-parkinsonian
drugs can be minimised.
Tardive Dyskinesia: As with all antipsychotic agents, 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 these 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 movements 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.
Other Undesirable Effects: As with other phenothiazines, drowsiness, lethargy, blurred
vision, dryness of the mouth, constipation, urinary hesitancy or incontinence, mild
hypotension, impairment of judgement and mental skills, and epileptiform attacks are
occasionally seen.

Headache, nasal congestion, vomiting, agitation, excitement, insomnia and
hyponatraemia have also been observed during phenothiazine therapy.
Blood dyscrasias have rarely been reported with phenothiazine derivatives. Blood counts
should be performed if the patient develops signs of persistent infection. Transient
leucopenia and thrombocytopenia have been reported. Antinuclear antibodies and SLE
have been reported very rarely.
Jaundice has rarely been reported. Transient abnormalities of liver function tests may
occur in the absence of jaundice.
A transient rise in serum cholesterol has been reported rarely in patients on oral
fluphenazine.
Abnormal skin pigmentation and lens opacities have sometimes been seen following
long-term administration of high doses of phenothiazines.
Phenothiazines are known to cause photosensitivity reactions but this has not been
reported for fluphenazine. Skin rashes, hypersensitivity and anaphylactic reactions
have occasionally been reported.
Elderly patients may be more susceptible to the sedative and hypotensive effects.
The effects of phenothiazines on the heart are dose-related. ECG changes with
prolongation of the QT interval and T-Wave changes have been reported commonly in
patients treated with moderate to high dosage; they have been reported to precede
serious arrhythmias, including ventricular tachycardia and fibrillation, which have also
occurred after overdosage. Sudden, unexpected and unexplained deaths have been
reported in hospitalised psychotic patients receiving phenothiazines.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases
of deep vein thrombosis have been reported with antipsychotic drugs – Frequency
unknown.
Phenothiazines may impair body temperature regulation. Elderly or hypothyroid patients
may be particularly susceptible to hypothermia. The hazard of hyperpyrexia may be
increased by especially hot or humid weather, or by drugs such as anti-parkinsonian
agents, which impair sweating.
Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported in
patients on neuroleptic therapy. The syndrome is characterised by hyperthermia, together
with some or all of the following: muscular rigidity, autonomic instability (labile blood
pressure, tachycardia, diaphoresis), akinesia, and altered consciousness, sometimes
progressing to stupor or coma. Leucocytosis, elevated CPK, liver function abnormalities,
and acute renal failure may also occur. Neuroleptic therapy should be discontinued
immediately and vigorous symptomatic treatment implemented since the syndrome is
potentially fatal.
Hormonal effects of phenothiazines include hyperprolactinaemia, which may cause
galactorrhoea, gynaecomastia and oligomenorrhoea or amenorrhoea. Sexual function

may be impaired, and false results may be observed with pregnancy tests. Syndrome
of inappropriate anti-diuretic hormone secretion has also been observed.
Oedema has been reported with phenothiazine medication.
Pregnancy, puerperium and perinatal conditions; drug withdrawal syndrome neonatal
(see section 4.6) – Frequency not known.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9

Overdose
Overdosage should be treated symptomatically and supportively,
extrapyramidal reactions will respond to oral or parenteral anti-parkinsonian
drugs such as procyclidine or benzatropine. In cases of severe hypotension, all
procedures for the management of circulatory shock should be instituted, e.g.
vasoconstrictors and/or intravenous fluids. However, only the vasoconstrictors
metaraminol or noradrenaline should be used, as adrenaline may further lower
the blood pressure through interaction with the phenothiazine.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics; Phenothiazines with piperazine
structure, ATC code: N05AB02
Fluphenazine decanoate is an ester of the potent neuroleptic fluphenazine, a
phenothiazine derivative of the piperazine type. The ester is slowly absorbed from the
intramuscular site of injection and is then hydrolysed in the plasma to the active
therapeutic agent, fluphenazine.
Extrapyramidal reactions are not uncommon, but fluphenazine does not have marked
sedative or hypotensive properties.

5.2

Pharmacokinetic properties
Plasma level profiles of fluphenazine following intramuscular injection have
shown half-lives of plasma clearance ranging from 2.5-16 weeks, emphasising
the importance of adjusting dose and interval to the individual requirements of
each patient. The slow decline of plasma levels in most patients means that a
reasonably stable plasma level can usually be achieved with injections spaced
at 2-4 week intervals.

5.3

Preclinical safety data
Not applicable

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Benzyl alcohol
Sesame oil

6.2

Incompatibilities
None

6.3

Shelf life
18 months
The in use shelf life for the 10ml vial is 28 days.

6.4

Special precautions for storage
Store below 25ºC.
Do not refrigerate or freeze.
Keep the ampoules in the outer carton in order to protect from light.

6.5

Nature and contents of container
Type I colourless glass ampoule containing 0.5, 1 and 2ml with an OPC (one point cut)
break system.
Type I Glass cartridge syringes with Helvoet Pharma rubber plungers and stoppers
containing 1 and 2ml.
Type I Glass vials with pharma-gummi rubber stoppers containing 10ml.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Aventis Pharma Limited

One Onslow Street
Guildford
Surrey
GU1 4YS
UK
or trading as:
Sanofi-aventis or Sanofi
One Onslow Street
Guildford
Surrey
GU1 4YS
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 04425/0386

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21/03/1996

10

DATE OF REVISION OF THE TEXT
06/01/2014