Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Zentiva k.s., U kabelovny 130, 102 37 Prague 10, Czech Republic
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Gamanil must not be used in patients hypersensitive to dibenzazepines.
Gamanil must not be used in patients:
Gamanil must not be administered with or within 2 weeks of cessation of therapy with monoamine oxidase inhibitors.
Gamanil must not be administered in patients with acute alcoholic, hypnotic, analgesic and psychotropic drug poisoning and acute deliria.
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide- related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which Gamanil is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old. Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Patients receiving anti-depressant therapy should be kept under regular surveillance with particular attention to the effects on cerebral function, haemopoietic function, cardiac conduction disorders.
Gamanil should be used with caution in patients with cardiovascular disease, because it is associated with a risk of cardiovascular adverse events in all age groups.
Moreover, caution is also required in patients with impaired liver or renal function, narrow angle glaucoma, symptoms suggestive of prostatic hypertrophy, a history of epilepsy or recent convulsions, hyperthyroidism, blood dyscrasias, porphyria or a susceptibility to paralytic ileus.
Caution is needed in patients with hyperthyroidism, or during concomitant treatment with thyroid preparations, since aggravation of unwanted cardiac effects occur.
Gamanil can prolong the QT-interval in the ECG and may lead to Torsades de Pointes. Gamanil may only be used with particular caution when other risk factors for Torsades de Pointes are present, such as:
which also prolong the QT interval in the ECG or can cause hypokalaemia. If Torsades de Pointes occurs the treatment with Gamanil has to be stopped.
Gamanil may lower the convulsion threshold; therefore extreme caution is necessary in patients with a history of epilepsy or recent convulsions or other predisposing factors, or during withdrawal from alcohol or other medicinal products with anticonvulsant properties.
Concurrent electroconvulsive therapy must only be undertaken with careful supervision.
Caution is recommended if Gamanil is used in patients with impaired liver function, impaired renal function, blood dyscrasias or porphyria.
Caution is recommended in patients with a history of prostatic hypertrophy, narrow angle glaucoma or increased intra-ocular pressure, because of Gamanil’s anticholinergic properties. In patients with narrow angle glaucoma. Gamanil may only be used if adequate glaucoma treatment is given.
In chronic constipation, Gamanil may cause paralytic ileus.
Caution is recommended in patients with tumours of the adrenal medulla in whom tricyclic antidepressants, such as Gamanil, may provoke hypertensive crises.
It is recommended that blood pressure be checked before initiating treatment because individuals with hypertension, or an unstable circulation, may react to Gamanil with a fall in blood pressure. Anaesthetics may increase the risks of arrhythmias and hypotension (see section 4.5), therefore before local or general anaesthesia, the anaesthetist must be informed that the patient has been taking Gamanil.
Caution is required in patients with a history of mania.
Psychotic symptoms may be aggravated. There have also been reports of hypomanic or manic episodes during a depressive phase in patients with cyclic affective disorders receiving tricyclic antidepressants including Gamanil.
It is recommended that abrupt withdrawal of Gamanil be avoided unless essential, because withdrawal symptoms may occur on abrupt cessation of therapy. Withdrawal symptoms may include insomnia, irritability and excessive perspiration. Monitoring of haemopoietic function is recommended particularly in patients with blood dyscrasias.
Gamanil contains lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine also contains Cochineal Red (E124), a colouring agent. This may cause allergic reactions. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’.
The elderly are particularly liable to experience adverse reactions to tricyclic antidepressants, especially agitation, confusion and rarely, postural hypotension.
Gamanil is not recommended for the treatment of children and adolescents under the age of 18 years.
Studies in depression in this age group did not show a beneficial effect for tricyclic antidepressants. Studies with other classes of antidepressants have shown a risk of suicidality, self-harm and hostility related to these compounds. This risk cannot be excluded with Gamanil.
Furthermore, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are not available.
MAO Inhibitors: Gamanil must not be administered with or within 2 weeks of cessation of therapy with monoamine oxidase inhibitors. Thereafter, cautious initiation of therapy is recommended using a low initial dose and the effects monitored.
Anti-arrhythmic agents: There is an increased risk of ventricular arrhythmias, which may lead to Torsades de Pointes if Gamanil is given with anti-arrhythmic agents which prolong the QT interval e.g. disopyramide, procainamide, propafenone, quinidine, sotalol and amiodarone. Particular caution is advised if Gamanil is used in combination with such agents.
Non-antiarrhythmic agents which may prolong the QT interval: There is an increased risk of ventricular arrhythmias which may lead to Torsades de Pointes if Gamanil is given with non- anti-arrhythmic agents which prolong the QT interval e.g. certain antibiotics (e.g. macrolides), cisapride, malaria agents, antihistamines (e.g. terfenadine), neuroleptic agents. Particular caution is advised if Gamanil is used in combination with such agents.
Medicinal products that may cause hypokalaemia: Combination with medicinal products that may cause hypokalaemia may increase the risk for ventricular arrhythmias including Torsades de Pointes. Particular caution is advised if Gamanil is used in combination with such agents.
Sympathomimetic agents: Concomitant use of Gamanil with sympathomimetic agents is not recommended since their cardiovascular effects may be potentiated.
Adrenergic neurone blockers: Gamanil may decrease or abolish the antihypertensive effects of some adrenergic neurone blocking drugs. Antihypertensive agents of a different type are therefore recommended where patients require co-medication for hypertension.
CNS depressants: Gamanil’s effects may be potentiated when administered with CNS depressant substances e.g. barbiturates, general anaesthetics and alcohol. If surgery is necessary, the anaesthetist should be informed that a patient is being so treated because of the increased risk of arrhythmias and hypotension.
Anti-cholinergic agents: Gamanil may potentiate the effects of these drugs on the central nervous system, eye, bowel and bladder.
SSRI Inhibitors: Co-medication may lead to additive effects on the serotonergic system. Fluvoxamine and fluoxetine may also increase plasma concentrations of Gamanil resulting in a lowered convulsion threshold and seizures.
Neuroleptic agents: In addition to an increased risk of arrhythmias, there may be an increased plasma level of the tricyclic antidepressant, a lowered convulsion threshold and seizures.
Anticoagulants: Gamanil may inhibit hepatic metabolism leading to an enhancement of anticoagulant effect. Careful monitoring of plasma prothrombin is advised.
Analgesics: There is an increased risk of ventricular arrhythmias.
Anti-epileptics: Antagonism can lead to a lowering of the convulsive threshold. Plasma levels of some tricyclic antidepressants, and therefore the therapeutic effect, may be reduced.
Calcium channel blockers: Diltiazem and verapamil may increase the plasma concentration of Gamanil.
Diuretics: There is an increased risk of postural hypotension.
Rifampicin: The metabolism of Gamanil is accelerated by rifampicin leading to a reduced plasma concentration.
Digitalis glycosides: With digitalis glycosides there is a higher risk of arrhythmias.
Cimetidine: Cimetidine can increase the plasma concentration of lofepramine.
Altretamine: There is a risk of severe postural hypotension when co-administered with tricyclic antidepressants.
Disulfiram and alprazolam: Co-medication with either disulfiram or alprazolam may require a reduction in the dose of Gamanil.
Nitrates: The effectiveness of sublingual nitrates may be reduced where the tricyclic antidepressant’s anticholinergic effect has lead to dryness of the mouth.
Ritonavir: There may be an increased plasma concentration of lofepramine.
Oral contraceptives: Oestrogens and progestogens may antagonize the therapeutic effect of tricyclic antidepressants. Adverse reactions of tricyclic antidepressants may be exacerbated due to an increased plasma concentration.
Thyroid hormone therapy: During concomitant treatment, there may be aggravation of unwanted cardiac effects.
The safety of Gamanil for use during pregnancy has not been established and there is evidence of harmful effects in pregnancy in animals when high doses are given. Lofepramine has been shown to cross the placenta. The administration of Gamanil in pregnancy is therefore not advised unless there are compelling medical reasons.
Adverse effects such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers have taken tricyclic antidepressants during the last trimester of pregnancy.
Lofepramine is excreted in breast milk. The administration of Gamanil during breast-feeding is not advised unless there are compelling medical reasons.
As with other antidepressants, the ability to drive a car and operate machinery may be affected, especially in conjunction with alcohol. Therefore caution is recommended initially until the individual reaction to treatment is known.
The adverse reactions reported with Gamanil are listed below by system organ class. 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) and not known (cannot be estimated from the available data).
Rarely: Bone marrow depression including isolated reports of: agranulocytosis, eosinophilia, granulocytopenia, leucopenia, pancytopenia, thrombocytopenia.
Rarely: Inappropriate secretion of antidiuretic hormone leading to hyponatraemia
Sleep disturbances, agitation, confusion, nightmares, hallucinations, hypomania, mania, psychoses, delirium. Cases of suicidal ideation and suicidal behaviours have been reported during Gamanil therapy or early after discontinuation (see section 4.4).
It should be remembered that severely depressed patients are at risk of suicide until there is a complete remission of symptomatology.
Dizziness, headache, paraesthesia, tremor.
Rarely: Drowsiness, convulsions, impairment of the sense of taste
Very Rarely: Uncoordinated movement.
Visual disturbances including blurred vision, mydriasis, disturbances of accommodation; induction of glaucoma
Very Rarely: Tinnitus
Tachycardia, cardiac conduction disorders, increase in cardiac insufficiency, QT-prolongation, arrhythmias (including ventricular arrhythmias or Torsades de Pointes.)
Hypotension
Gastrointestinal disturbances including nausea, vomiting, diarrhoea; constipation and dryness of mouth.
Raised liver enzyme levels, sometimes progressing to clinical hepatitis and jaundice, have been reported in some patients, usually occurring within the first 3 months of starting therapy
Skin rash, allergic skin reactions and "photosensitivity reactions"
Rarely: Cutaneous bleeding, sweating.
Urinary hesitancy, urinary retention.
Interference with sexual function, testicular disorders (e.g. testicular pain), gynaecomastia, galactorrhoea.
Malaise, facial oedema.
Rarely: Inflammation of mucosal membranes
Changes of blood sugar level
Some of the above mentioned adverse reactions may be due to the anticholinergic activity of Gamanil, these include:
Epidemiological studies, mainly in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRls and TCAs. The mechanism leading to this risk is unknown. The following adverse effects have been encountered in patients under treatment with tricyclic antidepressants and should therefore be considered as theoretical hazards of Gamanil even in the absence of substantiation: psychotic manifestations, including mania and paranoid delusions may be exacerbated during treatment with tricyclic antidepressants; withdrawal symptoms may occur on abrupt cessation of therapy and include insomnia, irritability and excessive perspiration; adverse effects such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers have taken tricyclic antidepressants during the last trimester of pregnancy.
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 HPRA Pharmacovigilance, Website: www.hpra.ie.
Not applicable.
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