Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
Anaphylactic shock
Single cases of anaphylactic shock have been reported.
Suicide/suicidal thoughts or clinical worsening
Depression is associated with a higher risk of suicidal thinking, self-damaging behaviour, and suicide (suicidality).
The risk persists until significant remission of the symptoms of depression occurs.
Patients should be monitored closely until remission because the recovery of the symptoms does not take place during the first weeks of treatment. General clinical experience has shown an increased risk of suicide during the early stages of remission.

Other psychiatric disorders which are treated with Anafranil could also lead to a higher risk of suicidality. In addition, such incidents could also occur together with a depressive disorder (episodes of a major depression).

When treating other psychiatric disorders, the same precautions should be maintained as when treating a depressive disorder.

The risk of suicidal thinking or suicide attempts is higher in patients with suicidality in their medical history or in patients who have been extremely suicidal before starting the treatment. Such patients should be monitored closely during the treatment. A meta-analysis of placebo-controlled studies with antidepressants in adults with psychiatric disorders have shown a higher risk of suicide in patients younger than 25 years compared to placebo.

Patients should be closely monitored during the initial phase of therapy or at times of dose changes, especially those patients with a higher risk.
Patients (and their caregivers) should be alerted about the need to monitor clinical worsening, suicidal behaviour or thinking and unusual changes in behaviour closely and in case of such symptoms seek medical advice immediately.

Patients with depressive disorders, both adult and paediatric, may experience worsening of depression and/or suicidality or other psychiatric symptoms, whether or not they are taking antidepressant medication.
Antidepressants increased the risk of suicidal thinking and behaviour (suicidality) in short-term studies in children, adolescents and young adults with depressive disorders and other psychiatric disorders.

When modifying the therapeutic regimen, including possibly discontinuation, those symptoms should be considered, especially if they are distinct or occur abruptly or are not part of the basic symptoms of the disorder (see “Treatment discontinuation” in the same section). Prescriptions for Anafranil should be written for the smallest quantity of tablets and patients should be closely monitored to reduce the risk of an overdose. Anafranil has been reported to be associated with fewer deaths following overdose than other tricyclic antidepressants.

Other psychiatric effects

Activation of psychosis has occasionally been observed in patients with schizophrenia receiving tricyclic antidepressants.

Hypomanic or manic episodes have also been reported during a depressive phase in patients with cyclic affective disorders receiving treatment with a tricyclic antidepressant. In such cases it may be necessary to reduce the dosage of the product or to withdraw it and administer an antipsychotic agent. After such episodes have subsided, low dose therapy with Anafranil may be resumed if required.

In predisposed patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses, particularly at night. These disappear within a few days of withdrawing the drug.
Cardiac and vascular disorders
Tricyclic antidepressants should be administered with caution in patients with cardiovascular disorders, especially those with cardiovascular insufficiency, conduction disorders, (e.g. atrioventricular block grades I to III), or arrhythmias. Monitoring of cardiac function and the ECG is indicated in such patients.

There may be a risk of QTc prolongation and torsades de pointes, particularly at supra- therapeutic doses or supra-therapeutic plasma concentrations of clomipramine, as occur in the case of co-medication with selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenergic reuptake inhibitors (SNRIs) (see sections 4.2 and 4.5). Therefore, concomitant administration of drugs that can cause accumulation of clomipramine should be avoided (see sections 4.2 and 4.5). It is established that hypokalemia is a risk-factor of QTc prolongation and torsades de pointes. Therefore, hypokalemia should be treated before initiating treatment with Anafranil (see section 4.2 and 4.5). Before starting treatment, it is advisable to check blood pressure because patients with postural hypotension or a labile circulation may experience a fall in blood pressure.

Serotonin syndrome
Due to the risk of serotonergic toxicity, it is advisable to adhere to the recommended doses. Concomitant administration of clopramine and other serotonergicagents such as Selective Serotonin re-Uptake Inhibitors (SSRIs), Serotonin Noreepinephrine Re-Uptake Inhibitors (SNRIs), tricyclic antidepressants, Buprenorphine or lithium may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5)

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities (myoclonus, seizures), gastrointestinal symptoms, hyperpyrexia, agitation, delirium, and coma.

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

A washout period of two to three weeks is advised before and after treatment with this fluoxetine.
If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Convulsions
Tricyclic antidepressants are known to lower the convulsion threshold. Anafranil should, therefore, be used with extreme caution in patients with epilepsy and other predisposing factors, e.g., brain damage of varying etiology, concomitant use of neuroleptics, withdrawal from alcohol or drugs with anticonvulsive properties (e.g., benzodiazepines). It appears that the occurrence of seizures is dose dependent. Therefore, the recommended total daily dose of Anafranil should not be exceeded.

Tricyclic antidepressants should be given with electroconvulsive therapy only under careful supervision.

Anticholinergic effects
Because of its anticholinergic properties, Anafranil should be used with caution in patients with a history of increased intraocular pressure, narrow-angle glaucoma, or urinary retention (e.g., diseases of the prostate).

Decreased lacrimation and accumulation of mucoid secretions due to the anticholinergic properties of tricyclic antidepressants may cause damage to the corneal epithelium in patients with contact lenses.

Specific treatment populations
Caution is called for when giving tricyclic antidepressants to patients with severe hepatic disease and tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma), in whom they may provoke hypertensive crises.
Caution is indicated in patients with hyperthyroidism or patients receiving thyroid preparations, owing to the possibility of enhanced cardiac toxicity due to its anticholinergic properties.

In patients with hepatic and renal disease, periodic monitoring of the hepatic enzyme levels and renal function is recommended.

Caution is called for in patients with chronic constipation when treated with Anafranil because it may cause paralytic ileus, particularly in elderly and in bedridden patients.

In elderly patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses, particularly at night. These disappear within a few days of withdrawing the drug.

Control of cardiovascular functions and the ECG are necessary in elderly patients.

An increase in dental caries has been reported during long-term treatment with tricyclic antidepressants.
Regular dental check-ups are therefore advisable during long-term treatment.
Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are not available.

Blood count
Although changes in the white blood cell count have been reported only in isolated cases, periodic blood cell counts and monitoring for symptoms such as fever, sore throat and other symptoms of a flu-like infection are called for, particularly during the first few months of therapy and during prolonged treatment.

Anesthesia
Before general or local anesthesia, the anesthetist should be told that the patient has been receiving Anafranil (see section 4.5).

Treatment discontinuation
Abrupt withdrawal should be avoided because of possible adverse reactions. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with serious symptoms (see section 4.8).

Lactose and sucrose
Anafranil 25 mg coated tablets contain lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, total lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Castor oil
Anafranil SR 75 mg film-coated tablets contain castor oil which may cause stomach upset and diarrhoea.

Effects on Driving

4.7   Effects on ability to drive and use machines

This medicinal product has a major impact on the ability to drive and use machines. Patients receiving Anafranil should be warned that blurred vision and other nervous system and psychiatric related disorders such as somnolence, disturbance in attention, confusion, aggravation of depression, delirium etc. (see section 4.8) have been observed. In the presence of such effects, patients should not drive, operate machinery, or do
anything else requiring alertness. Patients should also be warned that alcohol or other drugs may potentiate these effects (see section 4.5).