4.2 Posology and method of administration
Addition of following text:
Fluvoxamine should normally not be used to treat depressive illness in children and adolescents under 18 years of age (see section 4.4, Special Warnings and Precautions for Use).
4.4 Special warnings and precautions for use
Precautions for Use
Suicide/suicidal thoughts:
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 self harm is highest shortly after presentation and the risk of suicide may increase again in the early stages of recovery. Furthermore, there is evidence that in a small group of people, antidepressants may increase the risk of suicidal thoughts and self-harm. Other psychiatric conditions for which fluvoxamine 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, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults are at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Patients, (and caregivers of patients) should be alerted about the need to monitor for the emergence of suicidal thoughts and to seek medical advice immediately if these symptoms present.
Psychomotor restlessness:
The use of fluvoxamine has been associated with the development of psychomotor restlessness, which clinically may be very similar to akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental and it may be necessary to review the use of fluvoxamine.
Hepatic/renal insufficiency:
Patients suffering from hepatic or renal insufficiency should start on a low dose and be carefully monitored.
Treatment with fluvoxamine has rarely been associated with an increase in hepatic enzymes, generally accompanied by clinical symptoms. In such cases treatment should be discontinued.
Diabetes:
Fluvoxamine should be used with caution in patients with diabetes mellitus. Glycaemic control may be disturbed, especially in the early stages of treatment. The dosage of antidiabetic drugs may need to be adjusted.
Epilepsy:
Although in animal studies fluvoxamine has no pro‑convulsive properties, caution is recommended when the drug is administered to patients with a history of convulsive disorders. Fluvoxamine should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Treatment with fluvoxamine should be discontinued if seizures occur or if seizure frequency increases.
Glaucoma:
Fluvoxamine should be used with caution in patients with glaucoma, which may be exacerbated by SSRIs.
Serotonin syndrome/neuroleptic malignant syndrome:
On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome‑like events have been reported in association with treatment of fluvoxamine, particularly when given in combination with other serotonergic and/or neuroleptic drugs (see 4.8 Undesirable effects). As these syndromes may result in potentially life threatening conditions, treatment with fluvoxamine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated.
As with other SSRIs, hyponatremia has been rarely reported, and appears to be reversible when fluvoxamine is discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of reports were associated with older patients.
Coagulopathy:
There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most TCAs, aspirin, NSAIDs) as well as in patients with a history of bleeding disorders (particularly gastrointestinal bleeding) or coagulation disorders.
Mania/hypomania:
Fluvoxamine should be used with caution in patients with a history of mania/hypomania. Fluvoxamine should be discontinued in any patient entering a manic phase.
QT prolongation:
When combined with fluvoxamine plasma concentrations of terfenadine, or astemizole or cisapride may be increased resulting in an increased risk for QT‑prolongation/Torsade de Pointes. Therefore, fluvoxamine should not be co‑administered with these drugs.
Cardiac disease:
Due to lack of clinical experience special attention is advised in patients with cardiac disease and in the situation of post‑acute myocardial infarction.
Electroconvulsive therapy (ECT):
There is limited clinical experience of concomitant administration of fluvoxamine and ECT therefore caution is advisable.
Elderly:
Data in elderly subjects give no indication of clinically significant differences in normal daily dosages compared to younger subjects. However upward dose titration should be done slower in the elderly, and dosing should always be done with caution.
Children and adolescents under 18 years of age:
Due to lack of clinical experience the use of fluvoxamine in children for the treatment of depression cannot be recommended.
Long term safety data in children and adolescents especially related to growth, sexual function, cognitive and behavioural development are lacking. Careful monitoring is therefore recommended in this patient population.
Fluvoxamine should not be used in the treatment of children and adolescents under the age of 18 years, except for patients with OCD.
Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
Withdrawal:
Withdrawal symptoms seen on discontinuation of fluvoxamine treatment:
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8 Undesirable effects). In clinical trials adverse events seen on treatment discontinuation occurred in approximately 12% of patients treated with fluvoxamine. The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction.
Dizziness, sleep disturbances (including insomnia and intense dreams), nausea, headache and asthenia are the most commonly reported reactions.
Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within two weeks, though in some individuals they may be prolonged (two to three months or more). It is therefore advised that fluvoxamine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see "Withdrawal Symptoms Seen on Discontinuation of Fluvoxamine", Section 4.2 Posology and Method of Administration).
4.5 Interaction with other medicinal products and other forms of interaction
Fluvoxamine should not be used in combination with MAOIs (see also contraindications).
Pharmacokinetic interactions
Fluvoxamine is a potent inhibitor of CYP1A2, and to a lesser extent of CYP2C and CYP3A4. Drugs which are largely metabolised via these isoenzymes are eliminated more slowlyer and may have higher plasma concentrations when co‑administered with Fluvoxamine. This is particularly relevant for drugs with a narrow therapeutic index. Patients should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
Fluvoxamine has marginal inhibitory effects on CYP2D6 and seems not to affect non‑oxidative metabolism or renal excretion.
CYP1A2
An increase in previously stable plasma levels of those tricyclic antidepressants (e.g., clomipramine, imipramine, amitriptyline) and neuroleptics (e.g., clozapine, olanzapine) which are largely metabolised through cytochrome P450 1A2 when given together with fluvoxamine, has been reported. A decrease in the dose of these products should be considered if treatment with fluvoxamine is initiated. Patients co‑administered fluvoxamine and CYP1A2 metabolised drugs with a narrow therapeutic index (such as tacrine, theophylline, methadone, mexiletine) should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
Concomitant theophylline should be avoided if possible, or theophylline dosage halved.
When given with fluvoxamine, warfarin plasma concentrations were significantly increased and prothrombin times prolonged.
Isolated cases of cardiac toxicity have been reported when fluvoxamine was combined with thioridazine. Increased plasma concentrations of thioridazine as well as isolated cases of cardiac toxicity have been reported when fluvoxamine was combined with thioridazine. As plasma concentrations of propranolol are increased in combination with fluvoxamine, the propranolol dose may need to be lowered.
Caffeine plasma levels are likely to be increased during co‑administration with fluvoxamine. Thus, patients who consume high quantities of caffeine‑containing beverages should lower their intake when fluvoxamine is administered and adverse caffeine effects (like tremor, palpitations, nausea, restlessness, insomnia) are observed.
As plasma concentrations of ropinirole may be increased in combination with Fluvoxamine thus increasing the risk of overdose, surveillance and reduction in the posology of ropinirole during fluvoxamine treatment and after its withdrawal may be required.
Fluvoxamine may inhibit zolmitriptan metabolism; a reduction in zolmitriptan dosage may be necessary.
Fluvoxamine inhibits the metabolism of ropivacaine; prolonged administration of ropivacaine should be avoided.
CYP2C
Patients co‑administered fluvoxamine and CYP2C metabolised drugs with a narrow therapeutic index (such as phenytoin and proguanil) should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
CYP3A4
Plasma concentrations of tTerfenadine, and astemizole may be increased, with risk of QT interval prolongation and torsade de pointes, cisapride: see also special warnings and special precautions for use); avoid concomitant use. Patients co‑administered fluvoxamine and CYP3A4 metabolised drugs with a narrow therapeutic index (such as carbamazepine, ciclosporin) should be carefully monitored and, if necessary, dose adjustment of these drugs is recommended.
Oxidation
The plasma levels of oxidatively metabolised benzodiazepines (e.g. triazolam, rnidazolam, alprazolam, and diazepam) are likely to be increased when co‑administered with fluvoxamine. The dosage of these benzodiazepines should be reduced during co‑administration with fluvoxamine. Increased plasma levels of haloperidol have been reported. Reboxetine should not be given concurrently with fluvoxamine.
Glucuronidation
Fluvoxamine does not influence plasma concentrations of digoxin.
Renal excretion
Fluvoxamine does not influence plasma concentrations of atenolol.
Pharmacodynamic interactions
Alcohol: As with other psychotropic drugs patients should be advised to avoid alcohol use while taking fluvoxamine.
Anticoagulants and NSAIDs: In patients on oral anticoagulants, aspirin or other NSAIDs, and fluvoxamine, the risk for haemorrhage may increase and these patients should therefore be closely monitored.
Antiepileptics: SSRIs may antagonise the antiepileptic effect of antiepileptics.
Dopaminergics: At least two weeks should elapse between withdrawing fluvoxamine and starting selegiline. At least two weeks should elapse between withdrawing selegiline and starting fluvoxamine.
Lithium: Fluvoxamine has been used in combination with lithium in the treatment of severely ill, drug‑resistant patients. However, lithium (and possibly also tryptophan) enhances the serotonergic effects of fluvoxamine. The combination should be used with caution in patients with severe, drug‑resistant depression.
Other serotonergic agents: The serotonergic effects of fluvoxamine may be enhanced when used in combination with other serotonergic agents (Iincluding triptans, tramodol, SSRIs and St. John's Wort preparations) (see also special warnings and special precautions for use). Increased risk of CNS toxicity and serotonin syndrome with sibutramine; avoid concomitant use.
Fluvoxamine has been used in combination with lithium in the treatment of severely ill, drug‑resistant patients. However, lithium (and possibly also tryptophan) enhances the serotonergic effects of fluvoxamine. The combination should be used with caution in patients with severe, drug‑resistant depression.
In patients on oral anticoagulants and fluvoxamine, the risk for haemorrhage may increase and these patients should therefore be closely monitored.
As with other psychotropic drugs patients should be advised to avoid alcohol use while taking fluvoxamine.
4.8 Undesirable effects
Nausea, sometimes accompanied by vomiting, is the most frequently observed symptom associated with fluvoxamine treatment. This side effect usually diminishes within the first two weeks of treatment. Other adverse events, observed in clinical studies at frequencies listed below, are often associated with the illness and are not necessarily related to treatment.
Common (frequency 1-10 %):
Blood: Haemorrhage: (see also special warnings and special precautions for use)
Body: Asthenia, headache, malaise, weight gain or weight loss.
Cardiacovascular disorders: Palpitations/tachycardia, bradycardia, postural hypotension.
Digestive system: Abdominal pain, anorexia, constipation, diarrhoea, dry mouth, dyspepsia, nausea (sometimes accompanied by vomiting), liver function abnormality, taste perversion.
Eye: visual disturbances (including abnormal or blurred vision),
glaucoma.
Immune system: anaphylaxis and anaphylactoid reactions.
Metabolism and nutrition: polydipsia (rare), hypoglycaemia. As with other SSRIs, hyponatremia has been rarely reported, and appears to be reversible when fluvoxamine is discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion (see section 4.4 Special Warnings and Precautions for Use). The majority of reports were associated with older patients.
Musculoskeletal: Arthralgia, myalgia.
Nervous system: Agitation, anxiety, dizziness, insomnia, nervousness, somnolence, tremor, convulsions, mania, ataxia, confusion, extrapyramidal symptoms, hallucinations, paraesthesia,. Psychomotor restlessness/akathisia (see section 4.4 Special Warnings and Special Precautions for Use).
Psychiatric: Agitation, anxiety, confusion, nervousness, mania. Panic attacks, depersonalisation, hypomania, decreased libido have also been reported. Rarely, a serotonin syndrome characterised by at least three symptoms, including changes in psychiatric status and behaviour (excitement, confusion, anxiety, agitation, delirium and restlessness), motor dysfunction (tremor, rigidity, myoclonus, hyperreflexia, and ataxia), hypotension or hypertension and autonomic symptoms such as sweating, fever, shivering and diarrhoea may occur. Severe complications, including disseminated intravascular coagulation, respiratory failure, seizures and coma have also been reported (see also 4.4 Special warnings and precautions for use).
Skin: Sweating, photosensitivity, cutaneous hypersensitivity reactions (incl. rash, pruritius, angioedema, urticaria), cutaneous bleeding disorders (such as ecchymoses and purpura).
Renal and urinary: urinary retention.
Reproductive system and breast disorders: Abnormal (delayed) ejaculation, erectile dysfunction, anorgasmy, hyperprolactinaemia, galactorrhoea.
Uncommon (frequency < 1 %):
Cardiovascular: (Postural) hypotension
Musculoskeletal: Arthralgia, myalgia.
Nervous system: Ataxia, confusion, extrapyramidal symptoms, hallucinations
Urogenital: Abnormal (delayed) ejaculation, Galactorrhoea.
Skin: Cutaneous hypersensitivity reactions (incl. rash, pruritis, angioedema)
Rare (frequency < 0.1 %):
Digestive system: Liver function abnormality
Nervous system: Convulsions, mania
Urogenital. Galactorrhoea
Skin: Photosensitivity
Psychomotor restlessness/akathisia (see section 4.4 Special Warnings and Special Precautions for Use).
Other adverse events observed during marketing
Weight gain or weight loss have been reported.
Rarely, serotonin syndrome, neuroleptic malignant syndrome‑like events, hyponatremia and SIADH have been reported. (see also special warnings and special precautions for use).
It is possible that withdrawal reactions may occur on stopping therapy with fluvoxamine although the available preclinical and clinical evidence does not suggest that this treatment cause dependence. The following symptoms have been reported in association with withdrawal of the product: dizziness, paresthesia, headache, nausea and anxiety.
Haemorrhage: (see also special warnings and special precautions for use)
Very rarely, paresthesia, anorgasmy and taste perversion have been reported.
In one 10‑week placebo‑controlled trial in children and adolescents with OCD, frequently reported adverse events with a higher incidence than placebo, were: insomnia, asthenia, agitation, hyperkinesia, somnolence and dyspepsia. Serious adverse events in this study included: agitation and hypomania. Convulsions in children and adolescents have been reported during use outside clinical trials.
It is possible that withdrawal reactions may occur on stopping therapy with fluvoxamine although the available preclinical and clinical evidence does not suggest that this treatment cause dependence. The following symptoms have been reported in association with withdrawal of the product: dizziness, paresthesia, headache, nausea and anxiety.
Withdrawal symptoms seen on discontinuation of fluvoxamine treatment:
Discontinuation of fluvoxamine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sleep disturbances (including insomnia and intense dreams), nausea, headache, and asthenia, tremor and confusion are the most commonly reported reactions. Generally these events are mild to moderate and are self- limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when fluvoxamine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 Posology and Method of Administration and section 4.4 Special Warnings and Special Precautions for use).
4.9 Overdose
Symptoms
Symptoms include gastro‑intestinal complaints (nausea, vomiting and diarrhoea), somnolence and dizziness. Cardiac events (tachycardia, bradycardia, hypotension, electrocardiographic changes), liver function disturbances, convulsions, tremor,and coma, mydriasis, respiratory difficulties and hypokalemia have also been reported.
Fluvoxamine has a wide margin of safety in overdose. Since Between market introduction and 2000, when data was reviewed in the US, reports of death attributed to overdose of fluvoxamine alone hadve been extremely rare. The highest documented dose of fluvoxamine ingested by a patient is 12 gram. This patient recovered completely. Occasionally, more serious complications were observed in cases of deliberate overdose of fluvoxamine in combination with other drugs.
Treatment
There is no specific antidote to fluvoxamine. In case of overdose the stomach should be emptied as soon as possible after tablet ingestion and symptomatic treatment should be given. The repeated use of medicinal charcoal, if necessary accompanied by an osmotic laxative, is also recommended. The benefit of gut decontamination is uncertain, but oral activated charcoal can be considered if more than 1g has been ingested by an adult or 100mg by a child within 1 hour. Forced diuresis or dialysis are unlikely to be of benefit. It is important to maintain an adequate airway, oxygenation and ventilation and to monitor cardiac rhythm and vital signs following fluvoxamine overdose.
Single brief convulsions do not require treatment. Frequent or prolonged convulsions should be controlled with intravenous diazepam of lorazepam. Give oxygen and correct acid base balance and metabolic disturbances as required. Intravenous phenytoin may be useful if convulsions are unresponsive to these measures.
10 DATE OF REVISION OF THE TEXT
September 2006
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