Prochlorperazine Tablets Bp 5mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Prochlorperazine Tablets BP 5mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Prochlorperazine Maleate BP 5mg
Also contains lactose. For excipients, see section 6.1.
3 PHARMACEUTICAL FORM
White compressed tablets for oral administration
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Prochlorperazine Maleate is a potent phenothiazine neuroleptic. It is used in vertigo due to Meniere’s syndrome, labyrinthitis and for nausea and vomiting from whatever cause, including that associated with migraine, schizophrenia (particularly in the chronic stage), acute mania and as an adjunct to the short term management of anxiety.
There is little information about blood levels, distribution and excretion in humans. The rate of metabolism and excretion of phenothiazines decreases in old age.
4.2 Posology and method of administration Adults
Prevention of nausea and vomiting 5 to 10mg two or three times a day
Treatment of nausea and vomiting
20mg initially followed if necessary by 10mg two hours later.
Vertigo and Meniere’s syndrome
5mg three times a day increasing if necessary to a total of 30mg daily. After several weeks, dosage may be reduced gradually to 5-10mg daily.
Adjunct in the short-term management of anxiety
15-20mg daily in divided doses initially but this may be increased if necessary to a maximum of 40mg daily in divided doses.
Schizophrenia and other psychotic disorders
Usual effective daily oral dosage is in the order of 75-100mg daily.
Patients vary widely in response. The following schedule is suggested:
Initially 12.5mg twice daily for 7 days. The daily amount being subsequently increased by 12.5mg at four to seven day intervals until a satisfactory response is obtained.
After some weeks at the effective dosage, an attempt should be made to reduce this dosage.
Total daily amounts as small as 50mg or even 25mg have sometimes been found to be effective.
Children
Prevention and treatment of nausea and vomiting
If it is considered unavoidable to use Prochlorperazine maleate for a child, the dosage is 250 micrograms/kg bodyweight two or three times a day. Prochlorperazine maleate has been associated with dystonic reactions particularly after a cumulative dosage of 500 micrograms/kg. It should therefore be used cautiously in children. Prochlorperazine maleate is not recommended for children weighing less than 10kg or below 1 year of age.
Elderly
A lower initial dosage is recommended. See section 4.4.
4.3 Contraindications
Known hypersensitivity to Prochlorperazine or to any of the other ingredients. Prochlorperazine is contra-indicated in pregnancy.
4.4 Special warnings and precautions for use
Prochlorperazine maleate should be avoided in patients with liver or renal dysfunction, Parkinson’s disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis, prostate hypertrophy. It should be avoided in patients known to be hypersensitive to phenothiazines or with a history of narrow angle glaucoma or agranulocytosis. It should be used with caution in the elderly, particularly during very hot or very cold weather (risk of hyper-, hypothermia).
As agranulocytosis has been reported, regular monitoring of the complete blood count is recommended. The occurrence of unexplained infections or fever may be evidence of blood dyscrasia (see section 4.8), and requires immediate haematological investigation.
Close monitoring is required in patients with epilepsy or a history of seizures, as phenothiazines may lower the seizure threshold.
It is imperative that treatment be discontinued in the event of unexplained fever, as this may be a sign of neuroleptic malignant syndrome (pallor, hyperthermia, autonomic dysfunction, altered consciousness, muscle rigidity). Signs of autonomic dysfunction, such as sweating and arterial instability, may precede the onset of hyperthermia and serve as early warning signs. Although, neuroleptic malignant syndrome may be idiosyncratic in origin, dehydration and organic brain disease are predisposing factors.
Withdrawal symptoms
Acute withdrawal symptoms, including nausea, vomiting and insomnia, have very rarely been reported following the abrupt cessation of high doses of neuroleptics. Relapse may also occur, and the emergence of extra-pyramidal reactions has been reported. Therefore, gradual withdrawal is advisable.
QT interval prolongation
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 Prochlorperazine 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 Prochlorperazine and during the initial phase of treatment, or as deemed necessary during the treatment (see also sections 4.5 and 4.8).
Depression
As with all antipsychotic drugs, Prochlorperazine should not be used alone where depression is predominant. However, it may be combined with antidepressant therapy to treat those conditions in which depression and psychosis coexist.
Schizophrenia
In schizophrenia, the response to neuroleptic treatment may be delayed. If treatment is withdrawn, the recurrence of symptoms may not become apparent for some time.
Concomitant use of Prochlorperazine with other neuroleptics should be avoided.
Stroke
An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled clinical trials in the elderly dementia population with some atypical antipsychotics. The mechanism for this increased risk in not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Prochlorperazine should be used with caution in patients with risk factors for stroke.
Diabetes
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 Prochlorperazine, should get appropriate glycaemic monitoring during treatment (see section 4.8).
Venous Thrombo-embolism (VTE)
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 Prochlorperazine and preventive measures undertaken.
Hypotension
The elderly are particularly susceptible to postural hypotension. Prochlorperazine maleate should be used cautiously in the elderly owing to their susceptibility to drugs acting centrally on the nervous system. There is an increased risk of drug-induced Parkinsonism in the elderly particularly after prolonged use. Care should also be taken not to confuse the adverse effects of Prochlorperazine maleate e.g. orthostatic hypotension with effects due to the underlying disorder.
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.
Prochlorperazine is not licensed for the treatment of dementia-related behavioural disturbances.
Children
Prochlorperazine has been associated with dystonic reactions particularly after a cumulative dosage of 0.5mg/kg. It should therefore be used cautiously in children
Photosensitization
Because of the risk of photosensitisation, patients should be advised to avoid exposure to direct sunlight. To prevent skin sensitisation in those frequently handling preparations of phenothiazines, the greatest care must be taken to avoid contact of the drug with the skin (see section 4.8).
This product contains the excipient, lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
CNS depressants: The CNS depressant actions of neuroleptic agents may be intensified (additively) by alcohol, barbiturates and other sedatives. Respiratory depression may occur.
Antihypertensives: The hypotensive effect of most antihypertensive drugs especially alpha adrenoceptor blocking agents may be exaggerated by neuroleptics.
Phenothiazine neuroleptics: The action of some drugs may be opposed by phenothiazine neuroleptics; these include amphetamine, levodopa, clonidine, guanethidine, adrenaline.
Anticholinergic agents may reduce the antipsychotic effect of neuroleptics and the mild anticholinergic effect of neuroleptics may be enhanced by other anticholinergic drugs, possibly leading to constipation, heat stroke, etc.
Where treatment for neuroleptic-induced extrapyramidal symptoms is required, anticholinergic antiparkinsonian agents should be used in preference to levodopa, since neuroleptics antagonise the antiparkinsonian action of dopaminergics.
Some drugs interfere with absorption of neuroleptic agents; antacids, anti-Parkinson, lithium. Increases or decreases in the plasma concentrations of a number of drugs, e.g. propranolol, phenobarbitone have been observed but were not of clinical significance.
In patients treated concurrently with neuroleptics and lithium, there have been rare reports of neurotoxicity.
There is an increased risk of agranulocytosis when neuroleptics are used concurrently with drugs with myelosuppressive potential, such as carbamazepine or certain antibiotics and cytotoxics.
High doses of neuroleptics reduce the response to hypoglycaemic agents the dosage of which might have to be raised.
Adrenaline must not be used in patients overdosed with Prochlorperazine maleate. 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.
Concomitant use of Prochlorperazine with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Therefore, concomitant use of these products is not recommended. Examples include certain
• antiarrhythmics, such as those of Class IA (such as quinidine, disopyramide and procainamide) and
• Class III (such as amiodarone, sotalol and dofetilide)
• antimicrobials (such as sparfloxacin, moxifloxacin and erythromycin IV)
• tricyclic antidepressants (such as amitriptyline)
• tetracyclic antidepressants (such as maprotiline)
• other neuroleptics (e.g. phenothiazines, pimozide, sertindole and haloperidol)
• antimalarials such as quinine and mefloquine This list is not comprehensive.
Concurrent use of drugs causing electrolyte imbalance is not recommended. Diuretics, in particular those causing hypokalaemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.
4.6 Fertility, pregnancy and lactation
Prochlorperazine maleate is contra-indicated in pregnancy. There is inadequate evidence of the safety of Prochlorperazine maleate in human pregnancy but it has been widely used for many years without apparent ill consequence. There is evidence of harmful effects in animals.
Neonates exposed to antipsychotics (including Prochlorperazine) 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. Like other drugs it should be avoided in pregnancy unless the physician considers it essential. Neuroleptics may occasionally prolong labour and at such a time should be withheld until the cervix is dilated 3-4 cm. Possible adverse effects on the neonate include lethargy or paradoxical hyper-excitability, tremor and low apgar score.
Phenothiazines may be excreted in milk; breast feeding should be suspended during treatment.
4.7 Effects on ability to drive and use machines
Patients should be warned about drowsiness during the early days of treatment, and advised not to drive or operate machinery.
4.8 Undesirable effects
Generally, adverse reactions occur at a low frequency; the most common reported adverse reactions are nervous system disorders.
Minor side effects of neuroleptics are nasal stuffiness, dry mouth, insomnia, agitation.
Adverse effects of neuroleptics:
Hepatobiliary disorders: 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 (see section 4.4).
Vascular disorders: Hypotension, usually postural, commonly occurs. Elderly or volume depleted subjects are particularly susceptible; it is more likely to occur after intramuscular administration.
Respiratory, thoracic and mediastinal disorders: Respiratory depression is possible in susceptible patients.
Cardiac disorders: Arrhythmias including ventricular and atrial arrhythmia, A-V block, ventricular tachycardia and fibrillation or cardiac arrest have been reported rarely during neuroleptic therapy, possibly related to dosage, preexisting cardiac disease, old age, hypokalaemia and concurrent tricyclic antidepressants may predispose. ECG changes, usually benign, include widened QT interval, ST depression, U-waves and T-wave changes.
Sudden unexplained death, cardiac arrest and Torsades de pointes are class effects of neuroleptics.
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 the lymphatic system disorders: A mild leukopenia occurs in up to 30% of patients on prolonged high dosage. Agranulocytosis may occur rarely; it is not dose related. The occurrence of unexplained infections or fever requires immediate haematological investigation.
Nervous system disorders: 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 more common 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 subcutaneous tissue disorders: Contact skin sensitisation is a serious but rare complication in those frequently handling preparations of certain 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 the drug. Patients on high dosage should be warned that they may develop photosensitivity in sunny weather and should avoid exposure to direct sunlight.
Eye disorders: Ocular changes and the development of a metallic greyish-mauve colouration of exposed skin have been noted in some individuals mainly females, who have received chlorpromazine continuously for long periods (four to eight years). This could possibly happen with Prochlorperazine maleate.
Endocrine disorders: Hyperprolactinaemia which may result in galactorrhoea, gynaecomastia, amenorrhoea; impotence, intolerance to glucose, hyperglycaemia (see section 4.4).
General disorders and administration site conditions: Neuroleptic malignant syndrome (hyperthermia, rigidity, autonomic dysfunction and altered consciousness) may occur with any neuroleptic.
Pregnancy, puerperium and perinatal conditions
Drug withdrawal syndrome neonatal- frequency is not known.
4.9 Overdose
Symptoms of phenothiazines overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias and hypothermia. Severe extra-pyramidal dyskinesias may occur.
If the patient is seen sufficiently soon (up to 6 hours) after ingestion of a toxic dose, gastric lavage may be attempted. Pharmacological induction of emesis is unlikely to be of any use. Activated charcoal should be given. There is no specific antidote. Treatment is supportive.
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 superventricular tachy-arrhythmias usually respond to restoration of normal body temperature and correction of circulatory or metabolic disturbances. If persistent or life threatening, appropriate antiarrhythmic therapy may be considered. Avoid lignocaine 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: Antipsychotics ATC code: N05AB04
Prochlorperazine is a potent phenothiazine neuroleptic
Prochlorperazine has a wide range of activity arising from its depressant actions on the CNS and its alpha-adrenergic blocking and weaker antimuscarinic properties. It inhibits dopamine and prolactin-release-inhibitory factor, thus stimulating the release of prolactin. The turnover of dopamine in the brain is increased. There is evidence that the antagonism of central dopaminergic function is related to the therapeutic effect in psychotic conditions.
Prochlorperazine has sedative properties, but tolerance to the sedation usually develops rapidly. Prochlorperazine has anti-emetic, anti-pruritic, serotoninblocking, and weak anti-histaminic properties and slight ganglion-blocking activity. It inhibits the heat regulating centre, can relax smooth muscle and has membrane stabilising and hence local anaesthetic properties. Its actions on the autonomic system produce vasodilatation, hypotension and tachycardia. Salivary and gastric secretions are reduced.
5.2 Pharmacokinetic properties
Prochlorperazine is well absorbed from the GI tract, but is subject to first-pass metabolism in the gut wall and liver. It is excreted in urine and bile. Plasma concentrations following oral administration are much lower than those following intramuscular injection, and are subject to wide inter-subject variation. There is no simple correlation between plasma concentrations of prochlorperazine and its metabolites, and therapeutic effect. Prochlorperazine may be metabolised by hydroxylation and conjugation with glucuronic acid, N-oxidation, oxidation of the sulphur atom and dealkylation. Plasma half-life is reported to be only a few hours, but elimination of the metabolites may be very prolonged. Prochlorperazine is extensively bound to plasma proteins, widely distributed in the body (it crosses the blood/brain barrier) and its metabolites cross the placental barrier and are excreted in milk. The rate of metabolism and excretion decreases in old age.
5.3 Preclinical safety data
None presented
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose Maize starch Povidone
Sodium Starch Glycollate Magnesium stearate Microcrystalline Cellulose
6.2 Incompatibilities
None known
6.3 Shelf life
3 years - Polypropylene container 3 years - PVdC/Aluminium blister
6.4 Special precautions for storage
Store in a cool dry place and protect from light
6.5 Nature and contents of container
Polypropylene tubular container with an open end equipped to accept a polyethylene closure, with a tamper-evident strip in pack sizes of 7, 14, 21, 25, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120 and 1000 tablets
Or
PVdC coated PVC/Aluminium blisters (60g/m2 PVdC on 250p PVC/20p Al) in pack sizes of 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112 and 120
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
Norton Healthcare Limited Albert Basin,
Royal Docks,
London E16 2QJ
Trading as: Ivax Pharmaceuticals UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 00530/5067R
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
25/06/87
DATE OF REVISION OF THE TEXT
30/12/2011
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