Piportil Depot 50 Mg/Ml Solution For Injection
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Piportil Depot 50 mg/ml Solution for Injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1ml ampoule contains 50mg of the active substance pipotiazine palmitate.
Also contains 875mg/ml of sesame oil.
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for Injection A clear, yellow liquid.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the maintenance treatment of schizophrenia and paranoid psychoses and prevention of relapse, especially where compliance with oral medication is a problem
4.2 Posology and method of administration
Patients should be stabilised on Piportil Depot under psychiatric supervision. Administration should be by deep intramuscular injection into the gluteal region. A wide variation of response can be expected. The following dosage recommendations are suitable for either indication.
Adults: Initially 25mg should be given to assess the response of the patient to the
drug. Further doses should be administered at appropriate intervals, increasing by increments of 25 or 50 mg until a satisfactory response is obtained. In clinical practice, Piportil Depot has been shown to have a long duration of action, allowing intervals of 4 weeks between injections for maintenance therapy. Dosage should be adjusted under close supervision to suit each individual patient in order to obtain the best therapeutic response compatible with tolerance.
The duration of action depends on the dose administered, allowing dosage intervals to be varied to suit individual circumstances.
Most patients respond favourably to a dose of 50-100 mg every 4 weeks, the maximum recommended dose is 200 mg every four weeks.
Elderly : Neuroleptics should be used cautiously in the elderly: A reduced starting dose is recommended, i.e. 5-10 mg might be considered.
Children: Not recommended for use in children.
4.3 Contraindications
Piportil Depot should not be administered to patients in a comatose state or with marked cerebral atherosclerosis, phaeochromocytoma, renal or liver failure, severe cardiac insufficiency or hypersensitivity to other phenothiazine derivatives. Piportil Depot is also contraindicated in patients with hypersensitivity to pipotiazine palmitate or to any of the excipients.
4.4 Special warnings and precautions for use
Piportil Depot should be used with caution in patients suffering from or who have a history of, the following conditions: severe respiratory disease, epilepsy, alcohol withdrawal symptoms, brain damage, Parkinson's disease or marked extrapyramidal symptoms with previously used neuroleptics, personal or family history of narrow angle glaucoma, hypothyroidism, myasthenia gravis, prostatic hypertrophy, thyrotoxicosis. Care is required in very hot or very cold weather particularly in elderly frail patients.
Neuroleptic phenothiazines may potentiate QT interval prolongation which increases the risk of onset of serious ventricular arrhythmias of the torsade de pointes type, which is potentially fatal (sudden death). QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalaemia, and congenital or acquired (i.e. drug induced) QT prolongation. The risk-benefit should be fully assessed before Piportil treatment is commenced. If the clinical situation permits, medical and laboratory evaluations (e.g. biochemical status and ECG) should be performed to rule out possible risk factors (e.g. cardiac disease; family history of QT prolongation; metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia; starvation; alcohol abuse; concomitant therapy with other drugs known to prolong the QT interval) before initiating treatment with Piportil and during the initial phase of treatment, or as deemed necessary during the treatment (see also sections 4.5 and 4.8).
Avoid concomitant treatment with other neuroleptics (see section 4.5).
Stroke: In randomised clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical
antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism of such risk increase is not known. An increase in the risk with other antipsychotic drugs or other populations of patients cannot be excluded. Piportil should be used with caution in patients with stroke risk factors.
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.
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.
Piportil Depot is not licensed for the treatment of dementia-related behavioural disturbances.
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 Piportil Depot and preventative measures undertaken.
Hyperglycaemia or intolerance to glucose has been reported in patients treated with antipsychotic phenothiazines. Patients with an established diagnosis of diabetes mellitus or with risk factors for the development of diabetes, who are started on Piportil, should get appropriate glycaemic monitoring during treatment (see section 4.8).
4.5 Interaction with other medicinal products and other forms of interaction
There is an increased risk of arrhythmias when antipsychotics are used with concomitant QT prolonging drugs (including certain antiarrhythmics, antidepressants and other antipsychotics) and drugs causing electrolyte imbalance
The CNS depressant actions of neuroleptic agents may be intensified (additively) by alcohol, barbiturates and other sedatives. Respiratory depression may occur.
The hypotensive effect of most antihypertensive drugs especially alpha adrenoceptor blocking agents may be exaggerated by neuroleptics. This effect may also be observed with anaesthetics and opioid analgesics.
The mild anticholinergic effect of neuroleptics may be enhanced by other anticholinergic drugs possibly leading to constipation, heat stroke, etc.
The action of some drugs may be opposed by phenothiazine neuroleptics; these include amfetamine, levodopa, apomorphine, lisuride, pergolide, bromocriptine, cabergoline, clonidine, guanethidine, and adrenaline.
Some drugs may possibly enhance the effects of phenothiazines including cimetidine.
Anticholinergic agents may reduce the antipsychotic effect of neuroleptics.
Some drugs interfere with absorption of neuroleptic agents: antacids, kaolin, anti-Parkinson drugs, lithium. Increases or decreases in the plasma concentrations of a number of drugs, e.g. propranolol, phenobarbital have been observed but were not of clinical significance. Concomitant use with ritonavir may possibly increase the plasma concentration of the antipsychotic.
High doses of neuroleptics reduce the response to hypoglycaemic agents, the dosage of which might have to be raised.
There is an increased risk of extrapyramidal effects with tetrabenazine and lithium, and an increased possibility of neurotoxicity with lithium. Sibutramine can lead to an increased risk of CNS toxicity.
Adrenaline must not be used in patients overdosed with phenothiazine neuroleptics. Most of the above interactions are of a theoretical nature and not dangerous. Simultaneous administration of desferrioxamine and prochlorperazine has been observed to induce a transient metabolic encephalopathy characterised by loss of consciousness for 48--72 hours. It is possible that this may occur with Piportil since it shares many of the pharmacological properties of prochlorperazine.
Avoid concomitant use of Clozapine with depot formulation as it cannot be withdrawn quickly if neutropenia occurs.
4.6. Pregnancy and lactation
There is inadequate evidence of safety of Piportil Depot in human pregnancy, although animal studies have shown no hazard. The drug should not be used during pregnancy or lactation unless the physician considers it essential.
Neonates exposed to antipsychotics (including Piportil) 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.
4.7 Effects on ability to drive and use machines
Patients should be warned about drowsiness especially at the start of treatment and advised not to drive or operate machinery.
4.8 Undesirable effects
Minor side effects of neuroleptics are drowsiness, especially at the start of treatment, nasal stuffiness, dry mouth, insomnia, agitation and weight gain. Other possible adverse effects are listed below.
Liver function: jaundice, usually transient, occurs in a very small percentage of patients taking neuroleptics. A premonitory sign may be a sudden onset of fever after one to three weeks of treatment followed by the development of jaundice. Neuroleptic jaundice has the biochemical and other characteristics of obstructive jaundice and is associated with obstructions of the canaliculi by bile thrombi; the frequent presence of an accompanying eosinophilia indicates the allergic nature of this phenomenon. Treatment should be withheld on the development of jaundice.
Cardiorespiratory: Hypotension, usually postural, commonly occurs. Elderly or volume depleted subjects are particularly susceptible; it is more likely to occur after intramuscular administration.
ECG changes include QT prolongation (as with other neuroleptics), ST depression, U-Wave and T-Wave changes. Cardiac arrhythmias, including ventricular arrhythmias and atrial arrhythmias, a-v block, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest have been reported during neuroleptic phenothiazine therapy, possibly related to dosage. Pre-existing cardiac disease, old age, hypokalaemia and concurrent tricyclic antidepressants may predispose.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs - Frequency unknown
There have been isolated reports of sudden death, with possible causes of cardiac origin (see section 4.4), as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.
Blood picture: A mild leukopenia occurs in up to 30% of patients on prolonged high dosage of neuroleptics. Agranulocytosis may occur rarely; it is not dose-related. The occurrence of unexplained infections or fever requires immediate haematological investigation.
Extrapyramidal: Acute dystonias or dyskinesias, usually transitory, are commoner in children and young adults, and usually occur within the first 4 days of treatment or after dosage increases.
• Akathisia characteristically occurs after large initial doses.
• Parkinsonism is commoner in adults and the elderly. It usually develops after weeks or months of treatment. One or more of the following may be seen: tremor, rigidity, akinesia or other features of Parkinsonism. Commonly just tremor.
• Tardive dyskinesia: If this occurs it is usually, but not necessarily, after prolonged or high dosage. It can even occur after treatment has been stopped. Dosage should therefore be kept low whenever possible.
Skin and eyes: contact skin sensitisation is a serious but rare complication in those frequently handling preparations of phenothiazines; the greatest care must be taken to avoid contact of the drug with the skin. Skin rashes of various kinds may also be seen in patients treated with these drugs. Patients on high dosage should be warned that they may develop photosensitivity in sunny weather and should avoid exposure to direct sunlight.
Ocular changes and the development of a metallic greyish-mauve coloration of exposed skin have been noted in some individuals mainly females, who have received chlorpromazine continuously for long periods (four to eight years). Other neuroleptics have been implicated but less frequently.
Endocrine: hyperprolactinaemia which may result in galactorrhoea, gynaecomastia, amenorrhoea; impotence.
Neuroleptic malignant syndrome (hyperthermia, rigidity, autonomic dysfunction and altered consciousness) may occur with any neuroleptic.
Intolerance to glucose, hyperglycaemia (see section 4.4).
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
Symptoms of phenothiazine overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias and hypothermia. Severe extrapyramidal dyskinesias may occur. Generalised vasodilatation may result in circulatory collapse; raising the patient's legs may suffice, in severe cases, volume expansion by intravenous fluids may be needed; infusion fluids should be warmed before administration in order not to aggravate hypothermia.
Positive inotropic agents such as dopamine may be tried if fluid replacement is insufficient to correct the circulatory collapse. Peripheral vasoconstrictor agents are not generally recommended; avoid the use of adrenaline.
Ventricular or supraventricular tachy-arrhythmias usually respond to restoration of normal body temperature and correction of circulatory or metabolic disturbances. If they are persistent or life threatening, appropriate anti-arrhythmic therapy may be considered. Avoid lidocaine and, as far as possible, long acting anti-arrhythmic drugs.
Pronounced central nervous system depression requires airway maintenance or, in extreme circumstances, assisted respiration. Severe dystonic reactions usually respond to procyclidine (5--10mg) or orphenadrine (20--40mg) administered intramuscularly or intravenously. Convulsions should be treated with intravenous diazepam.
Neuroleptic malignant syndrome should be treated with cooling. Dantrolene sodium may be tried.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics; Phenothiazines with piperidine structure, ATC code: N05AC04.
Slow release phenothiazine neuroleptic
5.2 Pharmacokinetic properties
There is little information about blood levels, distribution and excretion in humans. The rate of metabolism and excretion of phenothiazines decreases in old age.
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sesame oil, Refined (containing butylhydroxyanisole - E320)
6.2 Incompatibilities
Piportil Depot injection should not be admixed with any other substance.
6.3 Shelf life
5 years
6.4 Special precautions for storage
Keep the ampoule in the outer carton in order to protect from light.
Nature and contents of container
6.5
1 and 2 ml clear glass ampoules- pack containing 10 ampoules. 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 04425/0585
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 27 August 1980 Date of latest renewal: 19 March 2002
07/02/2014