Bio-Sulpiride 200 mg Tablets

Schizophrenia. The management of acute episodes and the prevention of acute relapses in chronic cases.

Posology

Initial Treatment

200 to 800 mg orally in divided doses 8 or 12 hourly over 24 hours. Duration one to six weeks.

Maintenance treatment

600 to 800 mg per day (three to four BIO-SULPIRIDE 200 tablets) in divided doses. Duration as long as necessary. Plasma concentrations may be increased in elderly patients due to renal insufficiency (see section 4.4) for dosage adaption). There is a progressive reduction in the rate of elimination and an increase in half-life with decreasing renal function (see section 4.4). Patients with renal impairment or the elderly, with creatinine clearance of 30 to 60 ml/minute require a reduction of 70 % of normal dose, 10 to 30 ml/minute require a reduction of 50 % of normal dose and creatinine clearance of less than 10 ml/minute require a reduction of 35 % of normal dose. Alternatively, increase the dosage interval between doses by a factor of 1,5; 2 and 3, respectively.

Method of administration

For oral use.

• Hypersensitivity to sulpiride or to any of the excipients of BIO-SULPIRIDE 200, listed in section 6.1.
• BIO-SULPIRIDE 200 is contraindicated in patients with known or suspected phaeochromocytoma.
• Pregnancy and Lactation (see section 4.6).
• BIO-SULPIRIDE 200 should be avoided in patients with bone marrow depression.
• BIO-SULPIRIDE 200 should not be given with other medicines that may induce leucopenia and blood dyscrasias.
• Porphyria.
• Concomitant prolactin-dependent tumours e.g. pituitary gland prolactinomas and breast cancer.
• Congenital QT prolongation.
• Concomitant use with anti-Parkinson dopaminergic medicines (see section 4.5).

Initiation of treatment in schizophrenia should only be undertaken by a specialist under whose regular supervision the patients should remain. Neuroleptic malignant syndrome: In case of unexplained hyperthermia, it is essential to discontinue BIO-SULPIRIDE 200 since this may be indicative of the malignant syndrome described with neuroleptic medicines such as BIO-SULPIRIDE 200 (pallor, hyperthermia, vegetative disturbances, alteration of consciousness and muscle rigidity). Neuroleptic malignant syndrome may occur more frequently in catatonic schizophrenia. Symptoms of vegetative dysfunction such as sweating and unstable blood pressure can occur prior to the occurrence of hyperthermia and consequently represent early onset warning signs. Even though this neuroleptic-related adverse event can result from an individual idiosyncrasy to BIO-SULPIRIDE 200, certain risk factors appear to predispose to it such as dehydration or organic brain disease.

Prolongation of the QT interval: BIO-SULPIRIDE 200 produces a dose-dependent prolongation of the QT interval. This effect, known to potentiate the risk of serious ventricular dysrhythmias such as Torsades de Pointes, is enhanced by the presence of bradycardia, hypokalaemia, or congenital or acquired long QT interval as in combination with other medicines that increase the QT interval. Refer to section 4.5 for combinations of medicines with BIO-SULPIRIDE 200 which could induce u201cTorsades de Pointesu201d. Before administering BIO-SULPIRIDE 200, the absence of factors which can promote the occurrence of this dysrhythmias should be verified:

• Bradycardia less than 55 bpm
• Hypokalaemia
• Congenital prolongation of the QT interval
• Ongoing treatment with a medication which can cause marked bradycardia (< 55 bpm), hypokalaemia, slowing of intracardiac conduction or prolongation of the QT interval.

It is recommended to perform an ECG in the initial evaluation of patients who are to be treated with BIO-SULPIRIDE 200. Stroke: BIO-SULPIRIDE 200 should be used with caution in patients with stroke risk factors. BIO-SULPIRIDE 200 is not recommended in hypomanic patients, in the manic or pre-manic phase of manic-depressive psychosis, or in patients with acute mania, as BIO-SULPIRIDE 200 may precipitate manic states, which can last up to two days in certain patients prone to these conditions. If this should occur, BIO-SULPIRIDE 200 may either be discontinued or, if the therapeutic effect is required notwithstanding, BIO-SULPIRIDE 200 must be combined with sedative neuroleptics or other psychotropic medicines. Psychotic suicidal cases: BIO-SULPIRIDE 200, because of its disinhibitory effect, should be administered with care and combined with psychotherapy. Parkinsonu2019s disease: BIO-SULPIRIDE 200 should not be used in patients with Parkinsonu2019s disease (see section 4.5). BIO-SULPIRIDE 200 inhibits the action of levodopa and may potentiate the adverse effects of other antimuscarinics, including antimuscarinic anti-parkinsonian medicines.

Renal impairment: Patients with renal impairment, with creatinine clearance of 30 to 60 ml/minute require a reduction of 70 % of normal dose, 10 to 30 ml/minute require a reduction of 50 % of normal dose and creatinine clearance of less than 10 ml/minute require a reduction of 35 % of normal dose. Alternatively, increase the dosage interval between doses by a factor of 1,5; 2 and 3, respectively. Caution is required in patients with impaired liver, kidney or respiratory function, and in patients receiving other central nervous system depressant medicines, in whom central nervous system depression may be potentiated. Elderly patients: Elderly patients are more susceptible to postural hypotension, sedation and extrapyramidal effects. There is an increased mortality in elderly people with dementia who are treated with BIO-SULPIRIDE 200. BIO-SULPIRIDE 200 is not indicated for the treatment of dementia-related behavioural disturbances. In patients with aggressive behaviour or agitation with impulsiveness, BIO-SULPIRIDE 200 could be given with a sedative. BIO-SULPIRIDE 200 should only be administered with caution to patients with hypertension, especially in the elderly population, due to the risk of hypertensive crisis. Patients should be adequately monitored. BIO-SULPIRIDE 200 should be given with caution to patients in whom a sudden drop in blood pressure would be undesirable, and cardiovascular disorders. Concomitant use with medicines that produce postural hypotension may require dosage adjustments. The antihypertensive action of adrenergic neurone blockers is reduced by BIO-SULPIRIDE 200.

BIO-SULPIRIDE 200 effects on the vomiting centre may mask the symptoms of overdosage of other medicines, or of disorders such as gastrointestinal obstruction or congenital digestive stenosis. BIO-SULPIRIDE 200 should be given with care in patients with diabetes. Patients with an established diagnosis of diabetes mellitus or with risk factors for diabetes who are started on BIO-SULPIRIDE 200, should get appropriate glycaemic monitoring. BIO-SULPIRIDE 200 induces slight EEG modifications. Neuroleptics may lower the epileptogenic threshold and some cases of convulsions have been reported with BIO-SULPIRIDE 200 (see section 4.8 Undesirable Effects). Therefore, patients with a history of epilepsy should be closely monitored during BIO-SULPIRIDE 200 therapy. Care is required in epileptic patients receiving anticonvulsant therapy as BIO-SULPIRIDE 200 may lower the seizure threshold. In patients requiring BIO-SULPIRIDE 200 who are receiving anti-convulsant therapy, the dose of the anti-convulsant should not be changed. Cases of convulsions, sometimes in patients with no previous history, have been reported. Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including BIO-SULPIRIDE 200. Unexplained sore throat, lymphadenopathy, infections or fever may be evidence of blood dyscrasia (see section 4.8) and requires immediate haematological investigation. Patients receiving BIO-SULPIRIDE 200 therapy should receive regular examinations for abnormal ocular pigmentation or ocular changes. BIO-SULPIRIDE 200 has an anticholinergic effect and, therefore, should be used with caution in patients with a history of glaucoma, urine retention or hyperplasia of the prostate.

Venous thromboembolism: Cases of venous thromboembolism (VTE), sometimes fatal, have been reported with antipsychotic medicines. 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 BIO-SULPIRIDE 200 and preventative measures undertaken. Breast cancer: Sulpiride as contained in BIO-SULPIRIDE 200 may increase prolactin levels. Therefore, BIO-SULPIRIDE 200 should not be used in patients with a history or a family history of breast cancer or tumour of the pituitary gland (see section 4.3). Avoid concomitant prescription of other antipsychotics. In children, under the age of 18 years, efficacy and safety of BIO-SULPIRIDE 200 has not been established. Ingestion of alcohol as well as ingestion of any medication containing alcohol are strongly discouraged throughout duration of treatment with BIO-SULPIRIDE 200 (see section 4.5). BIO-SULPIRIDE 200 contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take BIO-SULPIRIDE 200.

Co-administration of BIO-SULPIRIDE 200 and the following combinations are contraindicated (see section 4.3):

Dopaminergic anti-Parkinson medicines: Amantadine, bromocriptine, cabergoline, levodopa, lisuride, pergolide, piribedil, ropinirole. Due to the reciprocal antagonism between these anti-Parkinson medicines and neuroleptics such as BIO-SULPIRIDE 200, concomitant use is contraindicated.

- In case of an extrapyramidal syndrome induced by BIO-SULPIRIDE 200, do not administer an anti-Parkinson dopaminergic medicine (blockade of dopaminergic receptors by neuroleptic medicines) to patients, but rather use an anticholinergic medicine (see section 4.4).

The following combination with BIO-SULPIRIDE 200 is not recommended:

Alcohol: The sedative effect of BIO-SULPIRIDE 200 can be enhanced by alcohol. Alteration of concentration can be dangerous when driving and/or operating machinery. The intake of alcohol and medications containing alcohol should be avoided.

Careful consideration should be given before administration of the following combinations:

Antihypertensive medicines: The antihypertensive effect and risk of postural hypotension are enhanced (additive effect).

Other central nervous system depressants: Morphine-related compounds; barbiturates; benzodiazepines; carbamates, etifoxine; hypnotic medicines; sedative antidepressants; sedative H1 histamine antagonists; central antihypertensive medicines; baclofen, thalidomide, other anxiolytics, clonidine and derivatives.

Antacids or sucralfate: The absorption of BIO-SULPIRIDE 200 is decreased after coadministration. Therefore, BIO-SULPIRIDE 200 should be administered two hours before these medicines.

Lithium: lithium increases the risk of extrapyramidal adverse reactions. Discontinuation of both medicines is recommended at first signs of neurotoxicity.

BIO-SULPIRIDE 200 may modify response to metoclopramide therapy. Concomitant administration of BIO-SULPIRIDE 200 with the following medication could induce Torsades de Pointes or prolong the QT interval:

• Medicines that induce electrolyte imbalance e.g. stimulant laxatives, tetracosactides, hypokalaemic diuretics, glucocorticoids and IV amphotericin B. The electrolyte balance of the patients should be corrected.
• Class Ia antidysrhythmic medicines such as quinidine, disopyramide.
• Class III antidysrhythmic medicines such as amiodarone, sotalol.
• Bradycardia-inducing medications such as beta-blockers, bradycardia-inducing calcium channel blockers such as diltiazem and verapamil, clonidine, digoxin, guanfacine.
• Methadone, pimozide, imipramine, haloperidol, antidepressants, pentamidine, halofantrine, lithium, cisapride, thioridazine, IV erythromycin, sultopride, bepridil, IV vincamine, sparfloxacin.

The use of alcoholic beverages and medicines containing alcohol should be avoided as alcohol enhances the sedative effects of BIO-SULPIRIDE 200.

The safety and/or efficacy of BIO-SULPIRIDE 200 during pregnancy and lactation has not been established.

Pregnancy

BIO-SULPIRIDE 200 is contraindicated during pregnancy (see section 4.3).

Breastfeeding

BIO-SULPIRIDE 200 is contraindicated during lactation (see section 4.3). BIO-SULPIRIDE 200 is excreted in breastmilk. Mothers on BIO-SULPIRIDE 200 should not breastfeed their infants.

Because of the drowsiness and impaired concentration that may ensue, affected patients should not drive or operate machines where loss of attention might be hazardous. Alteration of vigilance when using alcohol, and enhancement of central nervous system depression, is observed. Alteration of vigilance can occur when driving and using machines. The sedative effect must be fully assessed on the individual before driving or operating heavy machinery is allowed.

Tabulated list of adverse reactions

MedDRA System Organ Class

Immune system disorders

Frequency unknown: Anaphylactic reactions: urticaria, exfoliative dermatitis, and contact sensitivity, dyspnoea, hypotension, and anaphylactic shock

Blood and lymphatic system disorders

Less frequent: Leukopenia

Frequency unknown: Haematological disorders, including haemolytic anaemia, aplastic anaemia, thrombocytopenic purpura, eosinophilia, neutropenia and a potentially fatal agranulocytosis have been reported (see section 4.4).

Endocrine disorders

Frequent: Hyperprolactinaemia

Psychiatric disorders

Frequent: Insomnia

Frequency unknown: Confusion

Nervous system disorders

Frequent: Sedation or drowsiness, extrapyramidal symptoms, parkinsonism, tremor, akathisia

Less frequent: Hypertonia, dyskinesia, dystonia such as spastic oculogyric crisis

Frequency unknown: Malignant neuroleptic syndrome, hypokinesia, tardive dyskinesia, convulsion

Cardiac disorders

Less frequent: Ventricular dysrhythmias, ventricular fibrillation, ventricular tachycardia

Frequency unknown: Electrocardiogram QT prolonged, cardiac arrest, torsade de pointes, and sudden death (see section 4.4), tachycardia, electrocardiographic changes

Vascular disorders

Less frequent: Orthostatic hypotension

Frequency unknown: Hypertension, venous embolism, pulmonary embolism, deep vein thrombosis (see section 4.4)

Eye disorders

Frequency unknown: Mydriasis, miosis, blurred vision, pigmentary retinopathy, corneal and lens opacities

Respiratory, thoracic and mediastinal disorders

Frequency unknown: Pneumonia aspiration (mainly in association with other CNS depressants)

Reproductive system and breast disorders

Frequent: Breast pain, galactorrhoea

Less frequent: Breast enlargement, amenorrhoea, orgasm abnormal, erectile dysfunction

Frequency unknown: Impotence or frigidity, priapism, breast congestion, menstrual irregularities, gynecomastia

Metabolism and nutrition disorders

Frequency unknown: Hyperglycaemia, altered glucose tolerance and increased serum cholesterol concentrations, hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Renal and urinary disorders

Frequency unknown: Urinary retention

Gastrointestinal disorders

Frequent: Constipation

Less frequent: Salivary hypersecretion

Hepato-biliary disorders

Frequent: Hepatic enzyme increased

Frequency unknown: Abnormalities in liver function tests and jaundice, hepatocellular, cholestatic or mixed liver injury

Skin and subcutaneous tissue disorders

Frequent: Maculo-papular rash

Frequency unknown: Photosensitivity reactions

Musculoskeletal and connective tissue disorders

Frequency unknown: Torticollis, trismus, rhabdomyolysis

Pregnancy, puerperium and perinatal conditions

Frequency unknown: Extrapyramidal symptoms, drug withdrawal syndrome neonatal

General disorders and administration site conditions

Frequent: Weight gain

Frequency unknown: Hypo- and hyperthermia (see section 4.4), fatigue

Investigations

Frequency unknown: Blood creatine phosphokinase increased

Description of selected adverse reactions

Tardive dyskinesia: Characterised by rhythmic, involuntary movements primarily of the tongue and/or the face have been reported, as with all neuroleptics, after a neuroleptic administration of more than 3 months. Antiparkinsonian medication is ineffective or may induce aggravation of the symptoms).

Extrapyramidal symptoms and related disorders: Akinesia with or without hypertonia, and partially responsive to anticholinergic medicines, hyperkinetic-hypertonic syndrome, excitomotor syndrome, sleep disturbances, overstimulation and agitation, dry mouth and depression. The neuroleptic malignant syndrome (see section 4.4) is a life-threatening complication.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

In overdose, side effects will be exacerbated and exaggerated (see section 4.8). Dyskinetic manifestations with spasmodic torticollis, protrusion of the tongue and trismus may occur. Manifestations may vary depending on dose, and range from restlessness, clouding of consciousness, agitation, confusion. Some patients may develop life-threatening QT prolongation, Parkinsonian manifestations and coma. There is no specific antidote to BIO-SULPIRIDE 200. Administer symptomatic therapy, intensive care, under close and continuous monitoring of respiratory and cardiac functions (risk of prolongation of QT interval), which will be continued until the patientu2019s recovery. In cases of severe extrapyramidal symptoms, anticholinergics should be administered. BIO-SULPIRIDE 200 is partly removed by dialysis.