Novartis Pharmaceuticals UK Ltd

Unwanted effects are usually mild and transient, disappearing under continued treatment or with a reduction in the dosage. They do not always correlate with plasma drug levels or dose. It is often difficult to distinguish certain undesirable effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation, and dry mouth.

If severe neurological or psychiatric reactions occur, Anafranil should be withdrawn.

Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric, or cardiovascular effects.  Their ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.

The following side-effects, although not necessarily observed with Anafranil, have occurred with tricyclic antidepressants.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports unknown (frequency cannot be estimated from available data).

Table 1

¹      In post-marketing experience very rarely malignant neuroleptic syndrome has been reported although a causal relationship has not been confirmed.

²      Cases of suicidal ideation and suicidal behaviours have been reported during Anafranil therapy or early after treatment discontinuation (see section 4.4).

³      These adverse events were reported in patients treated with Anafranil based on post marketing reports.

Anticholinergic effects:

Very common: dryness of the mouth, sweating, constipation, disorders of visual accommodation and blurred vision, disturbances of micturition. 

Common: hot flushes, mydriasis. 

Very rare:  glaucoma. 

Central nervous system

Psychiatric effects:

Very common: drowsiness, transient fatigue, feelings of unrest, increased appetite.

Common: confusion accompanied by disorientation and hallucinations (particularly in geriatric patients and patients suffering from Parkinson's disease), anxiety states, agitation, sleep disturbances, mania, hypomania, aggressiveness, impaired memory, yawning, depersonalisation, insomnia, nightmares, aggravated depression, impaired concentration. 

Uncommon:  activation of psychotic symptoms. 

Frequency not known: suicidal ideation, suicidal behaviours.  Cases of suicidal ideation and suicidal behaviours have been reported during Anafranil therapy or early after treatment discontinuation (see section 4.4).

Neurological effects:

Very common: dizziness, tremor, headache, myoclonus.

Common: delirium, speech disorders, paraesthesia, muscle weakness, muscle hypertonia.

Uncommon: convulsions, ataxia. 

Very rare: EEG changes, hyperpyrexia. 

In post-marketing experience very rarely malignant neuroleptic syndrome has been reported although a causal relationship has not been confirmed.

Cardiovascular system:

Common: postural hypotension, sinus tachycardia, and clinically irrelevant ECG changes in patients of normal cardiac status (e.g. T and ST changes), palpitations. 

Uncommon: arrhythmias, increased blood pressure. 

Very rare: conduction disorders (e.g. widening of QRS complex, prolonged QTc interval, PQ changes, bundle-branch block), Torsade de Pointes, (particularly in patients with hypokalemia).

Gastro-intestinal tract:

Very common: nausea. 

Common: vomiting, abdominal disorders, diarrhoea, anorexia. 

Hepatic effects:

Common: elevated transaminases. 

Very rare: hepatitis with or without jaundice. 

Skin:

Common: allergic skin reactions (skin rash, urticaria), photosensitivity, pruritus. 

Very rare: local reactions after intravenous injections (thrombophlebitis, lymphangitis, burning sensation, and allergic skin reactions), oedema (local or generalised), hair loss. 

Endocrine system and metabolism:

Very common: weight gain, disturbances of libido and potency. 

Common: galactorrhoea, breast enlargement. 

Very rare: SIADH (inappropriate antidiuretic hormone secretion syndrome). 

Hypersensitivity:

Very rare: allergic alveolitis (pneumonitis) with or without eosinophilia, systemic anaphylactic/anaphylactoid reactions including hypotension.

Blood:

Very rare: leucopenia, agranulocytosis, thrombocytopenia, eosinophilia, and purpura.  

Sense organs:

Common: taste disturbances, tinnitus.

Withdrawal symptoms:

The following symptoms commonly occur after abrupt withdrawal or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness and anxiety (see section 4.4 Special warnings and precautions for use).

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRs and TCAs. The mechanism leading to this risk is unknown.

Elderly population

Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric, or cardiovascular effects. Their ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.

Central nervous system: drowsiness, stupor, coma, ataxia, restlessness, agitation, enhanced reflexes, muscular rigidity, choreoathetoid movements, convulsions, Sserotonin Ssyndrome (e.g. hypertensive crisis, hyperpyrexia, myoclonus, delirium and coma) may be observed.

Treatment of symptoms is based on modern methods of intensive care, with continuous monitoring of cardiac function, blood gases, and electrolytes and, if necessary, emergency measures such as:

- anticonvulsive therapy

- artificial respiration,

- insertion of a temporary cardiac pacemaker,

- plasma expander, dopamine or dobutamine administered by intravenous drip,

- resuscitation.

Pharmacotherapeutic group: Tricyclic antidepressant. Noradrenaline and preferential serotonin-reuptake inhibitor (non selective monoamine reuptake inhibitors), ATC code: N06A A04.

Mechanism of action

The therapeutic activity of Anafranil is believed to be based on its ability to inhibit the neuronal re-uptake of noradrenaline (NA) and serotonin (5-HT) released in the synaptic cleft, with inhibition of 5-HT reuptake being the more important of these activities.

Anafranil also has a wide pharmacological spectrum of action, which includes alpha1-adrenolytic, anticholinergic, antihistaminic, and antiserotonergic (5-HT-receptor blocking) properties.

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRs and TCAs. The mechanism leading to this risk is unknown.

•     Paragraph on treatment discontinuation added

• Paragraph on "use in children and adolescents (0-17 years of age)" added