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Core SPC Fluanxol® Depot 20 mg-ml, 100 mg-ml 200 mg-ml
Summary of product characteristics
NAME OF THE MEDICINAL PRODUCT
Fluanxol Depot 20 mg/ml solution for injectionFluanxol Depot 100 mg/ml solution for injectionFluanxol Depot 200 mg/ml solution for injection QUALITATIVE AND QUANTITATIVE COMPOSITION
Flupentixol decanoate 20 mg/ml.
Flupentixol decanoate 100 mg/ml.
Flupentixol decanoate 200 mg/ml.
For the full list of excipients, see section 6.1 Solution for injection Clear, colourless to slightly yellowish oil, practically free from particles.
Clear, yellowish to yellow oil, practically free from particles.
Clear, yellowish to yellow oil, practically free from particles.
Maintenance treatment of schizophrenia and other psychoses, especially with symptoms such as hallucinations, delusions and thought disturbances along with apathy, lack of energy, depression and withdrawal.
Posology and method of administration
PosologyAdultsDosage and interval between injections should be adjusted for each individual patient so as to achieve a maximum suppression of psychotic symptoms with a minimum of side effects.
Flupentixol decanoate 20 mg/ml In the maintenance treatment the dosage range would normally be 20-40 mg (1-2 ml) at intervals of 2 to 4 weeks depending on the response. Some patients may need larger doses or need them at shorter intervals. Flupentixol decanoate 20 mg/ml is unsuitable for patients in whom sedation is required. Injection volumes larger than 2 ml should be distributed between two injection sites.
If volumes larger than 2-3 ml of the 20 mg/ml solution are required the more concentrated solutions (flupentixol decanoate 100 mg/ml or 200 mg/ml) should be preferred.
During an exacerbation or acute relapse of the illness single injections of as much as 400 mg fortnightly (or in the occasional cases weekly for a short period) may be required.
Approved APR-2013Supersedes OCT-2012 Page 1 of 10 Flupentixol decanoate 100 mg/ml Dosage range lies between 50 mg (0.5 ml) every 4 weeks to 300 mg (3 ml) every 2 weeks but some patients may require up to 400 mg (4 ml) weekly. Injection volumes larger than 2 ml should be distributed between two injection sites.
Flupentixol decanoate 200 mg/ml Dosage range lies between 50 mg (0.25 ml) every 4 weeks to 300 mg (1.5 ml) every 2 weeks but some patients may require up to 400 mg (2 ml) weekly.
Adequate control of severe psychotic symptoms by the concentrated injection fluids is usually achieved within 4 to 6 months and may justify gradual return to lower dose maintenance.
When changing the medication from oral flupentixol to maintenance treatment with flupentixol decanoate the following guidelines should be used: x mg p.o. daily corresponds to 4x mg decanoate every 2 weeks.
x mg p.o. daily corresponds to 8x mg decanoate every 4 weeks.
Oral flupentixol should be continued during the first week after the first injection but in diminishing dosage.
Patients being transferred from other depot preparations should receive a dose in the ratio of 40 mg flupentixol decanoate equivalent to 25 mg fluphenazine decanoate, to 200 mg zuclopenthixol decanoate, or to 50 mg haloperidol decanoate.
Subsequent doses of flupentixol decanoate and interval between injections should be adjusted to the patient's response.
Older patientsOlder patients should receive dosages in the lower end of the dosage range.
Reduced renal functionFlupentixol decanoate can be given in usual doses to patients with reduced renal function.
Reduced liver functionCareful dosing and, if possible, a serum level determination is advisable.
ChildrenFlupentixol decanoate is not recommended for use in children due to lack of clinical experience.
Method of administrationFlupentixol decanoate is administered by intramuscular injection into the upper outer quadrant of the gluteal region. Injection volumes exceeding 2 ml should be distributed between two injection sites. Local tolerability is good.
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.
Special warnings and precautions for use
The possibility of development of neuroleptic malignant syndrome (hyperthermia, muscle rigidity, fluctuating consciousness, instability of the autonomous nervous system) exists with any neuroleptic. The Approved APR-2013Supersedes OCT-2012 Page 2 of 10 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.
Like other neuroleptics flupentixol decanoate should be used with caution in patients with organic brain syndrome, convulsion and advanced hepatic disease.
In the lower dosage range flupentixol decanoate is not recommended for excitable or overactive patients since its activating effect may lead to exaggeration of these characteristics.
As described for other psychotropics flupentixol decanoate may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients.
Patients on long-term therapy, particularly on high doses, should be monitored carefully and evaluated periodically to decide whether the maintenance dosage can be lowered.
As with other drugs belonging to the therapeutic class of antipsychotics, flupentixol decanoate may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, flupentixol decanoate should be used with caution in susceptible individuals (with hypokalemia, 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).
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Sincepatients treated with antipsychotics often present with acquired risk factors for VTE, all possiblerisk factors for VTE should be identified before and during treatment with flupentixol decanoate andpreventive measures undertaken 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.
Older people CerebrovascularAn approximately 3-fold increased risk of cerebrovascular adverse events have 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 decanoate should be used with caution in patients with risk factors for stroke.
Increased Mortality in Older people with DementiaData from two large observational studies showed that older people with dementia who aretreated with antipsychotics are at a small increased risk of death compared with those who are nottreated. There are insufficient data to give a firm estimate of the precise magnitude of the risk andthe cause of the increased risk is not known.
Flupentixol decanoate is not licensed for the treatment of dementia-related behavioural disturbances.
Approved APR-2013Supersedes OCT-2012 Page 3 of 10 Interaction with other medicinal products and other forms of interaction
Combinations requiring precautions for useFlupentixol decanoate may enhance the sedative effect of alcohol and the effects of barbiturates and other CNS depressants. Neuroleptics may increase or reduce the effect of antihypertensive drugs; the antihypertensive effect of guanethidine and similar acting compounds is reduced. Concomitant use of neuroleptics and lithium increases the risk of neurotoxicity. Tricyclic antidepressants and neuroleptics mutually inhibit the metabolism of each other.
Flupentixol decanoate may reduce the effect of levodopa and the effect of adrenergic drugs. Concomitant use of metoclopramide and piperazine increases the risk of extrapyramidal disorder.
Increases in the QT interval related to antipsychotic treatment may be exacerbated by the co-administration of other drugs known to significantly increase the QT interval. Co-administration of such drugs should be avoided. Relevant classes include:  class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)  some antipsychotics (e.g. thioridazine)  some macrolides (e.g. erythromycin)  some antihistamines (e.g. terfenadine, astemizole)  some quinolone antibiotics (e.g. gatifloxacin, moxifloxacin) The above list is not exhaustive and other individual drugs known to significantly increase QT interval (e.g. cisapride, lithium) should be avoided.
Drugs known to cause electrolyte disturbances such as thiazidediuretica (hypokalemia) and drugs known to increase the plasma concentration of flupentixol decanoate should also be used with caution as they may increase the risk of QT prolongation and malignant arrythmias (see section 4.4).
Fertility, pregnancy and lactation
PregnancyFlupentixol decanoate should not be administered during pregnancy unless the expected benefit to the patient outweighs the theoretical risk to the foetus.
Neonates exposed to antipsychotics (including flupentixol decanoate) 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-feedingAs flupentixol is found in breast milk in low concentrations it is not likely to affect the infant when therapeutic doses are used. The dose ingested by the infant is less than 0.5% of the weight related maternal dose (in mg/kg). Breast-feeding can be continued during flupentixol decanoate therapy if considered of clinical importance but observation of the infant is recommended, particularly in the first 4 weeks after giving birth. FertilityIn 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.
Approved APR-2013Supersedes OCT-2012 Page 4 of 10 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. Effects were seen at doses well in excess of those applied during clinical use.
Effects on ability to drive and use machines
Fluanxol Depot is a non-sedating drug in the low-moderate dosage range (up to 100 mg every second week).
However, patients who are prescribed psychotropic medication may be expected to have some impairment in general attention and concentration and should be cautioned about their ability to drive or operate machinery.
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. Extrapyramidal reactions may occur, especially during the first few days after injection and in the early phase of treatment. In most cases these side effects can be satisfactorily controlled by reduction of dosageand/or use of antiparkinsonian drugs. The routine prophylactic use of antiparkinsonian drugs is not recommended. Antiparkinsonian drugs do not alleviate tardive dyskinesia and may aggravate them. Reduction in dosage or, if possible, discontinuation of flupentixol therapy is recommended. In persistent akathisia a benzodiazepine or propranolol may be useful.
Frequencies are taken from the literature and spontaneous reporting. Frequencies are defined as: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), or not known (can not be estimated from the available data).
Blood and lymphatic system disorders Thrombocytopenia, neutropenia, leukopenia, agranulocytosis.
Immune system disorders Hypersensitivity, anaphylactic reaction.
Endocrine disorders 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.
Tardive dyskinesia, dyskinesia, parkinsonism, speech disorder, convulsion.
Neuroleptic malignant syndrome.
Accommodation disorder, vision abnormal.
Cardiac disorders Electrocardiogram QT prolonged.
Vascular disorders Hypotension, hot flush.
Venous thromboembolism Approved APR-2013Supersedes OCT-2012 Page 5 of 10 Respiratory, thoracic and mediastinal Salivary hypersecretion, constipation, vomiting, dyspepsia, diarrhoea.
Abdominal pain, nausea, flatulence.
Hepatobiliary disorders Liver function test abnormal.
Skin and subcutaneous tissue disorders Rash, photosensitivity reaction, dermatitis.
Musculoskeletal and connective tissue Muscle rigidity.
Renal and urinary disorders Micturition disorder, urinary retention.
Pregnancy, puerperium and perinatal Drug withdrawal syndrome neonatal Reproductive system and breast Ejaculation failure, erectile dysfunction.
Gynaecomastia, galactorrhoea, amenorrhoea.
General disorders and administration Asthenia, fatigue.
As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT prolongation, ventricular arrythmias - ventricular fibrillation, ventricular tachycardia, Torsade de Pointes and sudden unexplained death have been reported for flupentixol decanoate (see section 4.4).
Abrupt discontinuation of flupentixol decanoate 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 national reporting system (to be completed nationally).
Overdose
Due to the administration form overdose symptoms are unlikely to occur.
Symptoms: Somnolence, coma, movement disorders, convulsions, shock, hyperthermia/hypothermia.
ECG changes, QT prolongation, Torsade de Pointes, cardiac arrest and ventricular arrhythmias have been reported when administered in overdose together with drugs known to affect the heart.
Treatment: Treatment is symptomatic and supportive. Measures to support the respiratory and cardiovascular systems should be instituted. Epinephrine (adrenaline) should not be used as further lowering of blood pressure may result. Convulsions may be treated with diazepam and extrapyramidal symptoms with biperiden.
Approved APR-2013Supersedes OCT-2012 Page 6 of 10 Pharmacotherapeutic group:Neuroleptics (antipsychotics)ATCcode: N 05 AF 01 Mechanism of actionFlupentixol is a neuroleptic of the thioxanthene group.
The antipsychotic effect of neuroleptics is related to their dopamine receptor blocking effect but possibly also 5-HT (5-hydroxytryptamine) receptor blockade contributes. In vitro and in vivo flupentixol has high affinity for both dopamine D1 and D2 receptors whereas fluphenazine is almost D2 selective in vivo. The atypical antipsychotic, clozapine, shows - as flupentixol – equiaffinity to D1 and D2 receptors both in vitro and in vivo.
Flupentixol has high affinity for α1-adrenoceptors and 5-HT2 receptors, although lower than that of chlorprothixene, high-dose phenothiazines and clozapine, but no affinity for cholinergic muscarine receptors. It has only slight antihistaminergic properties and no α2-adrenoceptor blocking activity.
Flupentixol has proven to be a potent neuroleptic in all the behavioural studies for neuroleptic (dopamine receptor blocking) activity. Correlation is found in the in vivo test models, the affinity for dopamine D2 binding sites in vitro and the average, daily oral antipsychotic doses.
Perioral movements in rats are dependent on D1 receptor stimulation or blockade of the D2 receptor population. The movements can be prevented by flupentixol. Likewise, the results form investigations in monkeys indicate that oral hyperkinesia is more related to D1 receptor stimulation and to a less degree to D2 receptor supersensitivity. This leads to the suggestion that D1 activation is responsible for similar effects in man, i.e. dyskinesia. Therefore, blockade of D1 receptors should be advantageous.
Like most other neuroleptics, flupentixol increases the serum prolactin level.
Pharmacological studies have clearly demonstrated that flupentixol decanoate in oil has a prolonged neuroleptic effect and that the amount of drug necessary to maintain a certain effect over a long period is considerably smaller with the depot preparation than with daily oral administration of flupentixol. A very modest and short-lasting potentiation of barbiturate-induced sleeping time in mice could be demonstrated only with high doses. It is unlikely, therefore, that any significant interference with anaesthetics would occur in patients receiving the depot preparation.
Clinical efficacy and safetyIn clinical use flupentixol decanoate is intended for the maintenance treatment of chronic psychotic patients. The antipsychotic effect increases with increasing dosages. In low to moderate dosages (up to 100 mg/2 weeks) flupentixol decanoate is nonsedating while some unspecific sedation may be expected when higher doses are administered.
Flupentixol decanoate is particularly useful in the treatment of apathetic, withdrawn, depressed and poorly motivated patients.
Flupentixol decanoate permits continuous treatment especially of those patients who are unreliable in taking the oral medication prescribed for them. Flupentixol decanoate thus prevents the frequent relapses due to noncompliance in patients on oral medication.
AbsorptionBy esterification of flupentixol with decanoic acid flupentixol has been converted to a highly lipophilic substance, flupentixol decanoate. When dissolved in oil and injected intramuscularly the ester diffuses rather slowly from the oil to the body water phase where it is rapidly hydrolysed releasing the active flupentixol.
Approved APR-2013Supersedes OCT-2012 Page 7 of 10 Following intramuscular injection maximum serum concentration is generally reached over a period of 3-7 days. With an estimated half-life of 3 weeks (reflecting the release from the depot) steady state conditions will be attained after about 3 months' repeated administration. DistributionThe apparent volume of distribution (Vd)β is about 14.1 l/kg. The plasma protein binding is about 99 %.
BiotransformationThe metabolism of flupentixol proceeds along three main routes – sulphoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological activity. Flupentixol dominates over metabolites in brain and other tissues.
EliminationThe elimination half-life (T½ β) of flupentixol is about 35 hours and the mean systemic clearance (Cls) is about 0.29 l/min.
Flupentixol is excreted mainly with feces, but also to some degree with the urine. When tritium labelled flupentixol was administered to man the excretion pattern shows the excretion via feces to be about 4 times the urinary excretion.
In nursing mothers flupentixol is excreted in small amounts with the breast milk. The ratio milk conc./serum conc. in women is on an average 1.3.
LinearityThe kinetics is linear. The mean steady state pre-injection serum level of flupentixol corresponding to a 40 mg dose of flupentixol decanoate every 2 weeks is about 6 nmol/l.
Older patientsPharmacokinetic investigations have not been done in older patients. However, for the related thioxanthene drug, zuclopenthixol, the pharmacokinetic parameters are widely independent of the age of the patients.
Reduced renal functionBased on the above characteristics for elimination it is reasonable to assume that reduced kidney function is likely not to have much influence on the serum levels of parent drug. Reduced hepatic functionNo data available.
Pharmacokinetic / Pharmacodynamic relationshipA pre-injection serum (plasma) concentration of 1-3 ng/ml (2-8 nmol/l) and a max./min. fluctuation < 2.5 is suggested as a guideline for maintenance treatment of schizophrenic patients with a low-moderate degree of illness. Pharmacokinetically a dose of 40 mg/2 weeks of flupentixol decanoate is equivalent to a daily oral dose of 10 mg flupentixol.
Preclinical safety data
Acute toxicityFlupentixol has low acute toxicity.
Chronic toxicityIn chronic toxicity studies there were no findings of concern for the therapeutic use of flupentixol.
Reproductive toxicityIn fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats. Effects were seen at doses well in excess of those applied during clinical use.
Approved APR-2013Supersedes OCT-2012 Page 8 of 10 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.
CarcinogenicityFlupentixol has no carcinogenic potential.
Local toxicityThe local tolerability is good. Local muscle damage is seen after injection of aqueous solutions of neuroleptics. After intramuscular injection in rabbits of flupentixol decanoate in oil only slight haemorrhage and oedema was seen.
List of excipients
Triglycerides, medium-chain Flupentixol decanoate should not be mixed with depot formulations with sesame oil as the vehicle because this would result in definite changes in the pharmacokinetic properties of the involved preparations.
Shelf life
20 mg/mlAmpoules 100 mg/mlAmpoules 200 mg/mlAmpoules Special precautions for storage
Keep the ampoules in the outer carton in order to protect from light.
Nature and contents of container
20 mg/mlColourless glass (type I) ampoules of 1 ml and 2 ml.
Boxes of 1×1 ml, 4×1 ml, 6×1 ml and 10×1 ml, 1×2 ml and 10×2 ml.
100 mg/mlColourless glass (type I) ampoules of 0.5 ml and 1 ml.
Boxes of 1×0.5 ml and 10×0.5 ml, 1×1 ml and 10×1 ml.
200 mg/mlColourless glass (type I) ampoules of 1 ml and 2 ml.
Boxes of 5×1 ml and 5×2 ml.
Not all pack sizes may be marketed.
Approved APR-2013Supersedes OCT-2012 Page 9 of 10 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements MARKETING AUTHOTISATION HOLDER
H. Lundbeck A/SOttiliavej 92500 ValbyDenmark MARKETING AUTHORISATION NUMBER(S)
Fluanxol Depot 20 mg/ml solution for injection: AMM/069/18671 Fluanxol Depot 100 mg/ml solution for injection: AMM/069/18673 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Fluanxol Depot 20 mg/ml solution for injection: 22/12/2004 Fluanxol Depot 100 mg/ml solution for injection: 22/12/2004 DATE OF REVISION OF THE TEXT
Approved APR-2013Supersedes OCT-2012

Source: http://www.nmpb.gov.sd/reg/index.php/spc/Human%20medicines/SPC%20Doc/SPC%20Fluanxol%20Depot%2020%20100%20200%20mg%20per%20ml%20Portrait.pdf/download