SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Psytixol 200 mg/ml injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml ampoule contains 200 mg flupentixol decanoate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection.

A clear, colourless to pale yellow, oily solution for deep intramuscular use.

4 CLINICAL PARTICULARS

4.1    Therapeutic indications

Psytixol is indicated in the treatment of schizophrenia and other psychoses.

Use of flupentixol should be restricted to those stabilised on oral therapy.

4.2    Posology and method of administration

Posology

Adults:

The usual dosage of Psytixol is between 50 mg every 4 weeks and 300 mg every 2 weeks. However, some patients may require up to 400 mg weekly. The maximum single dose at any one time is 400 mg. For example, 800 mg ever 2 weeks should not be given. Other patients may be adequately maintained on dosages of 20-40 mg Psytixol every 2-4 weeks. For patients who have not previously received depot neuroleptics, treatment is usually started with a small dose (e.g. 20 mg) to assess tolerability. An interval of at least one week should be allowed before the second injection is given at a dose consistent with the patients’ condition.

Adequate control of severe psychotic symptoms may take up to 4 to 6 months at high enough dosage. Once stabilised lower maintenance doses may be considered, but must be sufficient to prevent relapse.

The appropriate presentation of Psytixol should be selected to achieve an injection volume which does not exceed 2 ml. Volumes greater than 2 ml should be distributed between two injection sites.

Elderly:

In accordance with standard medical practice, initial dosage may need to be reduced to a quarter or half the normal starting dose in the frail or older people.

Paediatric population:

Psytixol is not indicated for children.

Renal impairment

Flupentixol has not been studied in renal impairment. Increased cerebral sensitivity to antipsychotics has been noted in severe renal impairment (see section 4.4).

Hepatic impairment

Flupentixol has not been studied in hepatic impairment. It is extensively metabolised by the liver and particular caution should be used in this situation and serum level monitoring is advised (see section 4.4). Flupentixol should be initiated at low doses orally to check for tolerability before switching to the depot formulation.

Method of administration:

Deep intramuscular injection into the upper outer buttock or lateral thigh.

Dosage and dosage interval should be adjusted according to the patient’s symptoms and response to treatment.

Note: As with all oil based injections it is important to ensure, by aspiration before injection, that inadvertent intravascular entry does not occur.

4.3    Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Circulatory collapse, depressed level of consciousness due to any cause (e.g. intoxication with alcohol, barbiturates, or opiates), coma.

It is not recommended for excitable or agitated patients.

4.4    Special warnings and precautions for use

Caution should be exercised in patients having: liver disease; cardiac disease or arrhythmias; severe respiratory disease; renal failure; epilepsy (and conditions predisposing to epilepsy e.g. alcohol withdrawal or brain damage); Parkinson's disease; narrow angle glaucoma; prostatic hypertrophy; hypothyroidism; hyperthyroidism; myasthenia gravis; phaeochromocytoma and patients who have shown hypersensitivity to thioxanthenes or other antipsychotics.

As with other drugs belonging to the therapeutic class of antipsychotics, flupentixol may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, flupentixol should be used with caution in susceptible individuals (with hypokalaemia, hypomagnesia or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (<50 beats per minute), a recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.

Concomitant treatment with other antipsychotics should be avoided (see section 4.5). Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including flupentixol decanoate.

Long-acting depot antipsychotics should be used with caution in combination with other medicines known to have a myelosuppressive potential, as these cannot rapidly be removed from the body in conditions where this may be required.

Cerebrovascular:

An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations.

Flupentixol should be used with caution in patients with risk factors for stroke.

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 Psytixol and preventative measures undertaken.

Elderly:

Older people may require close supervision as they are especially prone to experience such adverse effects as sedation, hypotension, confusion and temperature changes such as hypothermia.

Neuroleptic malignant syndrome (characterised by hyperthermia, muscle rigidity, fluctuating consciousness, instability of the autonomous nervous system) exists with any neuroleptic. The risk is possibly greater with the more potent agents. Patients with pre-existing organic brain syndrome, mental retardation, and opiate and alcohol abuse are over-represented among fatal cases.

Treatment: Discontinuation of the neuroleptic. Symptomatic treatment and use of general supportive measures. Dantrolene and bromocriptine may be helpful.

Symptoms may persist for more than a week after oral neuroleptics are discontinued and somewhat longer when associated with the depot forms of the drugs.

Blood dyscrasias, including thrombocytopenia, have been reported rarely. Blood counts should be carried out if a patient develops signs of persistent infection.

As described for other psychotropics flupentixol may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients.

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. The plasma concentrations of the flupentixol gradually decrease over several weeks which make gradual dosage tapering unnecessary.

Extrapyramidal reactions in the form of acute dystonias (including oculogyric crisis), parkinsonian rigidity, tremor, akinesia and akathisia have been reported and may occur even at lower dosage in susceptible patients. Such effects would usually be encountered early in treatment, but delayed reactions may also occur. In most cases, these side effects can be satisfactorily controlled by reduction of dosage and/or use of antiparkinson agents.

Antiparkinson agents should not be prescribed routinely because of the possible risk of precipitating toxic-confusional states, impairing therapeutic efficacy or causing anticholinergic side-effects. They should only be given if required and their requirement reassessed at regular intervals.

Tardive dyskinesia can occur with neuroleptic treatment. It is more common at high doses for prolonged periods but has been reported at lower dosage for short periods. The risk seems to be greater in older people, especially females. It has been reported that fine vermicular movements of the tongue are an early sign. It has been observed occasionally in patients receiving flupentixol. Antiparkinson drugs do not alleviate tardive dyskinesia and the concurrent use of anticholinergic anti-parkinson drugs may exacerbate this effect. The potential irreversibility and seriousness, as well as the unpredictability of the syndrome, requires especially careful assessment of the risk versus benefit, and the lowest possible dosage and duration of treatment consistent with therapeutic efficacy. Reduction in dosage or, if possible, discontinuation of flupentixol therapy is recommended. In persistent akathisia a benzodiazepine or propranolol may be useful. Short-lived dyskinesia may occur after abrupt withdrawal of the drug.

When transferring patients from oral to depot antipsychotic treatment, the oral medication should not be discontinued immediately, but gradually withdrawn over a period of several days after administering the first injection.

Increased mortality in older people with dementia

Data from two large observational studies showed that older people with dementia who are treated with antipsychotics are at a small increased risk of death compared to 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.

Flupentixol is not licenced for the treatment of dementia-related behavioural disturbances.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Flupentixol is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

4.5 Interaction with other medicinal products and other forms of interaction

In common with other neuroleptics, flupentixol enhances the response to alcohol, the effects of barbiturates and other CNS depressants. Flupentixol may potentiate the effects of general anaesthetics and anticoagulants and prolong the action of neuromuscular blocking agents.

Antipsychotics may antagonise the effects of adrenaline and other sympathomimetic agents, and reverse the antihypertensive effects of guanethidine and similar adrenergic-blocking agents.

Antipsychotics may impair the effect of levodopa, adrenergic drugs and anticonvulsants.

The metabolism of tricyclic antidepressants may be inhibited and the control of diabetes may be impaired.

The anticholinergic effects of atropine or other drugs with anticholinergic properties may be increased.

Concomitant use of drugs such as metoclopramide, piperazine or antiparkinson drugs may increase the risk of extrapyramidal symptoms such as tardive dyskinesia.

Antipsychotics may enhance the cardiac depressant effects of quinidine; the absorption of corticosteroids and digoxin. The hypotensive effect of vasodilator antihypertensive agents such as hydralazine and a-blockers (e.g. doxazosin), or methyldopa may be enhanced.

Combined use of antipsychotics and lithium or sibutramine has been associated with an increased risk of neurotoxicity.

Concomitant use of flupentixol with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsades de pointes. Therefore concomitant use of these products is not recommended.

Examples of drugs known to prolong the QT interval include:

Certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide) and Class III (such as amiodarone, sotalol, bretylium and dofetilide), some quinolone antibiotics (e.g. moxifloxacin), some macrolides (e.g. erythromycin), tricyclic antidepressants, antipsychotics (e.g. phenothiazines, pimozide, sertindole, haloperidol, thioridazine), some antihistamines, cisapride and certain antimalarials such as quinine and mefloquine.

The above list is not exhaustive and other individual drugs known to significantly increase QT interval (e.g. lithium) should be avoided.

Drugs known to cause electrolyte disturbances such as thiazide diuretics (hypokalaemia) and drugs known to increase the plasma concentration of flupentixol should also be used with caution as they may increase the risk of QT prolongation and malignant arrhythmias (see section 4.4). If necessary, potassium-sparing diuretics are preferred.

4.6 Fertility, pregnancy and lactation

Pregnancy

As the safety of this drug during pregnancy has not been established, use during pregnancy, especially the first and last trimesters should be avoided unless the expected benefit to the patient outweighs the potential risk to the foetus.

Neonates exposed to antipsychotics (including Psytixol) 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.

Animal studies have shown reproductive toxicity (see section 5.3).

Breast-feeding

Flupentixol is excreted into the breast milk. If the use of Psytixol is considered essential, nursing mothers should be advised to stop breast-feeding.

Fertility

In humans, adverse events such as hyperprolactinaemia, galactorrhoea, amenorrhoea, libido decreased, erectile dysfunction and ejaculation failure have been reported (see section 4.8). These events may have a negative impact on female and/or male sexual function and fertility.

If clinical significant hyperprolactinaemia, galactorrhoea, amenorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation.

In preclinical fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats (see section 5.3).

4.7 Effects on ability to drive and use machines

Alertness may be impaired, especially at the start of treatment, or following the consumption of alcohol; patients should be warned of this risk and advised not to drive or operate machinery until their susceptibility is known. Patients should not drive if they have blurred vision.

4.8 Undesirable effects

Cases of suicidal ideation and suicidal behaviours have been reported during flupentixol therapy or early after treatment discontinuation (see section 4.4).

Undesirable effects are for the majority dose dependent. The frequency and severity are most pronounced in the early phase of treatment and decline during continued treatment.

Cases of QT prolongation, VF, VT or ventricular arrhythmias (rare), cardiac arrest, sudden unexplained death and torsades de pointes have been reported. These adverse effects are class effects of neuroleptics (see also Section 4.4).

ECG changes with prolongation of the QT interval and T-wave changes may occur with moderate to high doses; they are reversible on reducing the dose.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs - frequency unknown.

Blood and lymphatic system disorders	Thrombocytopenia, neutropenia, leucopenia, agranulocytosis
Immune system disorders	Hypersensitivity, anaphylactic reaction
Endocrine disorder	Hyperprolactinaemia
Metabolism and nutrition disorders	Increased appetite, weight increased Decreased appetite Hyperglycaemia, glucose tolerance abnormal
Psychiatric disorders	Insomnia, depression, nervousness, agitation, libido decreased Confusional state.
Nervous system disorders	Somnolence, akathisia, hyperkinesia, hypokinesia Tremor, dystonia, dizziness, headache, disturbance in attention Tardive dyskinesia, dyskinesia, parkinsonism, speech disorder, convulsion Neuroleptic malignant syndrome
Eye disorders	Accommodation disorder, vision abnormal Oculogyration
Cardiac disorders	Tachycardia, palpitations Electrocardiogram QT prolonged

Vascular disorders	Hypotension, hot flush
Respiratory, thoracic and mediastinal disorders	Dyspnoea
Gastrointestinal disorders	Dry mouth Salivary hypersecretion, constipation, vomiting, dyspepsia, diarrhoea Abdominal pain, nausea, flatulence
Hepatobiliary disorders	Liver function test abnormal Jaundice
Skin and subcutaneous	Hyperhidrosis, pruritus
tissue disorders	Rash, photosensitivity reaction, dermatitis
Musculoskeletal and	Myalgia
connective tissue disorder	Muscle rigidity
Renal and urinary disorders	Micturition disorder, urinary retention
Pregnancy, puerperium and perinatal conditions	Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and	Ejaculation failure, erectile dysfunction
breast disorders	Gynaecomastia, galactorrhoea, amenorrhoea
General disorders and	Asthenia, fatigue
administration site conditions	Injection site reaction

Abrupt discontinuation of flupentixol may be accompanied by withdrawal symptoms. The most common symptoms are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety, and agitation.

Patients may also experience vertigo, alternate feelings of warmth and coldness, and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Overdosage may cause somnolence, or even coma, extrapyramidal symptoms, convulsions, hypotension, shock, hyper-or hypothermia. ECG changes, QT prolongation, Torsades de Pointes, cardiac arrest and ventricular arrhythmias have been reported when administered in overdose together with drugs known to affect the heart.

Treatment is symptomatic and supportive, with measures aimed at supporting the respiratory and cardiovascular systems. The following specific measures may be employed if required.

anticholinergic antiparkinson drugs if extrapyramidal symptoms occur.

-    sedation (with benzodiazepines) in the unlikely event of agitation or excitement or convulsions.

-    noradrenaline in saline intravenous drip if the patient is in shock. Adrenaline must not be given.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Neuroleptics (antipsychotics), ATC code: N05AF01 Mechanism of action

Flupentixol is a non-sedating neuroleptic drug of the thioxanthene group. Its primary pharmacological action is dopamine blockade. Flupentixol has a high affinity for Dj and D₂ receptors. Psytixol contains the deconoic ester of flupentixol in thin vegetable oil.

5.2    Pharmacokinetic properties

After intramuscular injection, the ester is slowly released from the oil depot and is rapidly hydrolysed to release flupentixol. Flupentixol is widely distributed in the body and extensively metabolised in the liver. Peak circulating levels occur around 7 days after administration.

The serum concentration curve declines exponentially and a half-life of 17 days reflects the slow release of the drug from the depot. It may take up to nine weeks following cessation of therapy before Flupentixol is not detectable in the serum.

Flupentixol is widely distributed throughout the body with maximum concentration in the liver, lungs, intestines and kidneys. Lower concentrations are found in the heart, spleen, brain and blood. More than 95% of the drug is bound to plasma proteins and the volume of distribution is 14.1 kg-1.

5.3 Preclinical safety data

Reproductive toxicity

In fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats. Animal reproduction studies in mice, rats and rabbits have not shown evidence of teratogenic effects. Embryotoxic effects in terms of increased post implantation loss/increased absorption rates or occasional abortions were seen in rats and rabbits at doses associated with maternal toxicity..

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Triglycerides, medium chain

Incompatibilities

Psytixol should not be mixed with any other injection fluids.

6.3    Shelf life

2 years

6.4    Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5    Nature and contents of container

Type I amber glass ampoules containing 1 ml or 2 ml of 20 mg/ml flupentixol decanoate.

The ampoules are available in packs of 1, 5 or 10 ampoules.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal and other handling

No special requirements

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd t/a Mylan Station Close

Potters Bar, Herts, EN6 1TL - UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/0395

9    DATE OF FIRST AUTHORISATION/RENEWAL OF    THE

AUTHORISATION

Date of first authorisation: 21/05/2001 Date of latest renewal: 07/01/2009

10 DATE OF REVISION OF THE TEXT

14/09/2016