AFLUDITEN 25 mg/ml

Fluphenazini decanoas 25 mg in 1 mL of injection solution

Complete list of excipients, see the Part 6.1

Injection solution
Clear, light yellow oil solution.


4.1 Therapeutic indications
Maintenance treatment of psychotic disorders in adults, teenagers and children older than 12 years.

4.2. Posology and method of administration
Optimal dose and frequency of administration for adults and teenagers must be determined according to the individual therapeutic response of the patient. It is advantageous to start the treatment in hospitalized patients, however it is not a condition. In most patients it is recommended to start with the dose of 12.5 to 25 mg (0.5 to 1 mL). One injection is sufficient for the maintenance treatment lasting 4 weeks, in some patients even 6 weeks. The dose should not exceed 100 mg. If it is shown that the patient needs the dose higher than 50 mg, the following doses should be increased carefully by 12.5 mg.
Children older than 12 years are applied usually the half of the dose for adults. The starting dose is 6.25 mg (0.25 mL), this dose can be increased progressively according to the therapeutic response of patient. 
The dose sufficient for elderly patients makes 1/4 to 1/3 of the dose for adults and teenagers.
At the change from the treatment by per oral drug the previous maintenance dose of per oral neuroleptics is reduced and at the first time the half of ampoule content (12.5 mg) of AFLUDITEN 25 mg/mL is applied deep into muscle. The same dose is applied after 14 days and at the same time the per oral medication is decreased progressively. Finally the regular maintenance dose of 25 mg of AFLUDITEN 25mg/mL once in 4 weeks is applied. Only rarely it is necessary to apply this dose in three-week intervals.
AFLUDITEN 25 mg/mL is applied intramuscularly or subcutaneously by a dry syringe and needle. Use of wet syringe or needle can cause a turbidity of solution.

4.3. Contraindications 
Hypersensitivity to drug substance or excipients. In patients with known hypersensitivity to other phenothiazine compounds the attention must be paid, because the cross-hypersensitivity cannot be excluded. 
AFLUDITEN 25 mg/mL is contraindicated at impairment, or suspicion of organic brain impairment, at application of high doses with buffering effect on central nervous system (alcohol, barbiturates, narcotics, hypnotics), at comatose or heavy depressive states, at extra-pyramidal disorders. Liver impairment, blood dyscrasia.
AFLUDITEN 25 mg/mL is not applied to pregnant and breast-feeding women and to children younger than 12 years.
Relative contraindications are chronic diseases of heart and kidneys, Parkinson disease, glaucoma, prostatic hypertrophy, malignant neuroleptic syndrome in anamnesis and symptoms of tardive dyskinesia or dystaxia, epilepsy. 

4.4. Special warnings and precautions for use
Relative contraindications are chronic heart and kidneys diseases, Parkinson disease, glaucoma, prostatic hypertrophy, malignant neuroleptic syndrome in anamnesis and symptoms of tardive dyskinesia or dystaxia, epilepsy. 
At the treatment by neuroleptics tardive dyskinesia may occur in some patients, the syndrome consisting of potentially irreversible involuntary dyskinetic movements. Although the incidence of this syndrome is most frequent in patients of older age, mainly in women, it cannot be assumed however in which patient it will appear. The syndrome can occur also after a short-time medication in low doses. Treatment of tardive dyskinesia is not known, at discontinuation of neuroleptics application it is usually retreated completely or partially. Application of neuroleptics including fluphenazine can suppress the symptoms of syndrome to a great extent, and so to mask the running disease process. Therefore the chronic treatment by neuroleptics should be prescribed to the patients with known therapeutic response to these drug substances, by which the alternatively effective but probably the safer medication is not suitable or available. These patients should be given the lowest doses in shortest possible time. At the same time, the necessity of further chronic treatment has to be checked regularly. If the signs and symptoms of tardive dyskinesia appear, the application of neuroleptics has to be discontinued.
At the treatment by neuroleptics the potentially fatal complex of the symptom called neuroleptic malignant syndrome was described. Its clinical symptoms are hyperpyrexia, muscular rigidity, changed mental condition and apparent autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and heart dysrhythmia). Treatment of this syndrome includes immediate discontinuation of application of antipsychotic drugs and other drugs unimportant at the therapy, intensive treatment of symptoms, medical observation of patient and treatment of all present serious health problems, if the specific treatment if suitable. Nowadays there is no general consensus on specific pharmacological treatment regimen for uncomplicated neuroleptic malignant syndrome.
If the patient requires further the antipsychotic treatment after extinction of neuroleptic malignant syndrome, the suitability of further medication must be considered carefully and the patient must be monitored thoroughly. 
In connection with antipsychotics the cases of venous thromboembolism (VTE). As the patients treated by antipsychotics have always the acquired risk factors for VTE, it is necessary to identify all risk factors for VTE before, as well as during the treatment by AFLUDITEN 25 mg/mL and to accept the necessary preventive measures. 

Increased mortality in older patients with dementia
The results of two extensive research studies have shown that the older patients with dementia, who are treated with antipsychotics, have slightly increased death risk compared to those patients who are not treated with them. At the present time, the sufficient data on reliable estimation of risk measure and the reason of increased risk is not known.
AFLUDITEN 25 mg/mL is not suitable for treatment of behavior disorders associated with dementia.

4.5. Interaction with other medicinal products and other forms of interaction 
Phenothiazines can increase the attenuation of CNS induced by alcohol, hypnotics, sedatives or analgesics and antagonize the effect of adrenalin and other sympathomimetics, also guanethidine and clonidine. The drug reduces the effect of L-dopa, anticonvulsants, biotransformation of tricyclic antidepressants and can worsen the compensated diabetes. Interaction with lithium can be shown neurotoxically. 

4.6. Fertility, pregnancy and lactation
The drug is not administered in pregnancy, because its safety has not been proven. Fluphenazine passes into breast milk; in infants it can cause weakness, skin exanthema and very rarely cholestatic icterus. 
In newborns who were during the third trimester in pregnancy exposed to effect of antipsychotic drugs (including the medicinal product AFLUDITEN 25 mg/mL), there is a risk of undesirable effects including extrapyramidal symptoms and/or withdrawal symptoms. These symptoms may differ in duration and in severity. The cases of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory anxiety or food-intake disorders were reported. Therefore the newborns have to be monitored carefully.

4.7. Effects on ability to drive and use machines
The drug may affect the ability of patient to drive and use machines, particularly at the beginning of the treatment.

4.8. Undesirable effects
Central nervous system – the most common are extrapyramidal disorders (pseudoparkinsonism, dystonia, dyskinesia, akathisia, oculogyric crisis, opistotonus, hyperreflexia). 
Tardive dyskinesia, neuroleptic malignant syndrome, somnolence, lethargy, headache, pseudo-depressions can occur. 
Hypertension, blood pressure variations. Rarely hypotension.
Endocrine and metabolic disorders – change of body weight, peripheral edema, abnormal lactation, gynecomastia, irregular menstruation, impotency in man and libido changes in women, false pregnancy test results.
Allergic reactions – skin disorders (itching, urticaria, seborrhea, photosensitivity, eczema and exfoliative dermatitis). Asthma, laryngeal edema, angioneurotic edema occur rarely.
Hematologic reactions – blood dyscrasias (leucopenia, agranulocytosis, thrombocytopenic or non-thrombocytopenic purpura, eosinophilia, pancytopenia). If there appears any pain in mouth, gums or neck, if the symptoms of upper airways infection occur and if bone marrow depression occurs at blood count control, the application must be discontinued.
Liver disorders – cholestatic jaundice (medication must be discontinued).
Other adverse effects – unexpected and unexplainable deaths after application of phenothiazines were reported. Predisposing factor is previous brain injury or epileptic fits.
Other uncommon reactions – lupus erythematosus-like syndrome and EKG change. At long-time administration skin pigmentations, turbidity of lens and cornea.
In connection with antipsychotics the cases of venous thromboembolism, including pulmonary embolism and deep venous thrombosis were reported. Frequency is unknown.
Conditions in pregnancy, puerperium and perinatal period – drug withdrawal syndrome in newborns (see the Point 4.6). Frequency unknown.

4.9. Overdose
Overdose symptoms are demonstrated by emphasized pharmacological and adverse reactions as well, particularly serious extrapyramidal reactions, hypotension and attenuation. Attenuation of central nervous system may continue till occurrence of coma and areflexion. 
Light overdose syndromes are restlessness, confusion and excitation. At overdose it is necessary to discontinue immediately the application of the drug and the symptoms must be treated with supporting measures. If hypotension appears, the application of anti-hypotensivum is suitable; at serious extrapyramidal reactions it is necessary to begin (and also continue for several weeks) with the medication of antiparkinsonian drugs. Haemodialysis is not efficient, therapeutically effective is hemoperfusion. 


5.1. Pharmacological properties

Pharmacotherapeutic group: neuroleptic, antipsychotic drug
ATC code: N05AB02

Fluphenazine shows the activity at all levels of central nervous system, but also of other organ systems. Mechanism of therapeutic efficacy is not known, but is put into connection with antidopaminergic drug effects. Main effects of decanoate are not different from the effects of fluphenazine chloride excepting the effect length. Esterification of fluphenazine prolongs significantly the effect length of the pharmaceutical drug.

5.2. Pharmacokinetic properties
Like other antipsychotic substances, fluphenazine is also characterized with interindividual variability of pharmacokinetic parameters. Intramuscular application guarantees optimal absorption and biological availability. Interindividual variance of pharmacokinetic data and relationship between dose and therapeutic response may be influenced by age, genetic factors and interactions with other medicinal products. 
Fluphenazine is biotransformed to a great measure. It is subject to biotransformation in liver (“first pass effect”) and is excreted in urine and stool. In plasma is it from more than 90 % bound to plasmatic proteins. Through esterification of fluphenazine with long chain fatty acid and through dissolution of ester in sesame oil the diffusion and availability of free active substance from the injection site is decelerated. Peak plasmatic concentrations are reached in the first 24 hours after intramuscular injection. Generally the effect onset is 24 to 72 hours after injection application and the effect on psychosis symptoms occurs within 48 to 96 hours. Serum biological half-life is about 7 to 10 days.
Phenothiazines pass through hemato-encephalic barrier, cross easily the placental barrier and cannot be removed by dialysis. 

5.3. Preclinical safety data
Neuroleptics increase the level of prolactin which persists during the whole application period. By in vitro experiments the connection between increased prolactin level and breast carcinoma was proven, one third of breast carcinoma is prolactin-dependent. In rodents the connection between long-time application of neuroleptics and incidence of mammary gland carcinoma was proven. Data on connection between long-time application of neuroleptics and incidence of breast carcinoma in human are not known.


6.1. List of excipients
Alcohol benzylicus, sesami oleum pro iniectione

6.2. Incompatibilities
Injection AFLUDITEN 25 mg/mL must not be mixed with other medicinal products.

6.3. Shelf life
3 years

6.4. Special precautions for storage 
Store below 25 ºC. Do not freeze. Store in original package in order to protect from light. 

6.5. Nature and contents of container
Brown glass ampoule (1 mL), formed plastic moulding, label, box.
Package size: 5 x 1 mL

6.6. Instructions for use and other handling
AFLUDITEN 25 mg/mL is applied intramuscularly or subcutaneously by a dry syringe and needle.
Use of wet syringe or needle can cause a turbidity of solution.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

BB Pharma a.s., Pod Višňovkou 1662/21, Prague, Czech Republic
68/0012/76-S, 68/012/76-S/C
27.07.1976 /15.11.2006 – without limitation of validity
September 2013