Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Unwanted effects do not always correlate with plasma drug levels or dose. It is often difficult to distinguish certain undesirable effects from symptoms of the treated disorder (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If severe neurological or psychiatric reactions occur, Anafranil should be withdrawn.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 metabolize and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.

Adverse reactions are ranked under heading of system organ class and frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000) very rare (< 1/10,000); not known (frequency cannot be estimated from the available data).

The ADRs tabulated below are based on clinical trial results as well as post- marketing reports.

Blood and lymphatic system disorders
Very rare               Leukopenia, agranulocytosis, thrombocytopenia, eosinophilia Immune system disorders
Very rare               Anaphylactic and anaphylactoid reactions including hypotension Endocrine disorders
Very rare               Inappropriate antidiuretic hormone secretion (SIADH) Metabolism and nutrition disorders
Very common             Increased appetite, weight gain
Psychiatric disorders
Very common             Restlessness, libido disorder, erectile dysfunction Common                  Confusional state, disorientation, hallucinations (particularly in elderly patients and patients with Parkinson's disease), anxiety, agitation, sleep disorder, mania, hypomania, aggression, depersonalisation, aggravation of depression, insomnia, nightmares, delirium, nervousness
Uncommon                Activation of psychotic symptoms
Not known               Suicidal thinking and behaviour (single cases of suicidal thinking and behaviour have been reported during or shortly after treatment with clomipramine (also see section 4.4.)).
Nervous system disorders
Very common             Fatigue, light-headedness, dizziness, tremor, headache, myoclonus, Common                  Memory impairment, disturbance in attention, speech disorder, paraesthesia, hypertonia, dysgeusia
Uncommon                Convulsions, ataxia
Very rare               EEG changes, neuroleptic malignant syndrome
Eye disorders
Very common             Accommodation disorder, vision blurred
Common                   Mydriasis
Very rare                Glaucoma
Ear and labyrinth disorders
Common                   Tinnitus
Cardiac disorders
Common                   Sinus tachycardia, palpitation
Uncommon                 Arrhythmias
Very rare                Conduction disorder (e.g. widening of QRS complex, prolonged QT interval, PQ changes, bundle-branch block, torsade de pointes, particularly in patients with hypokalaemia)
Vascular disorders
Common                   Hot flush, orthostatic hypotension
Very rare                Hypotension
Respiratory, thoracic, and mediastinal disorders
Common                   Yawning
Very rare                Alveolitis allergic (pneumonitis) with or without eosinophilia Gastrointestinal disorders
Very common              Dry mouth, constipation, nausea,
Common                   Vomiting, gastrointestinal disorder, diarrhoea, decreased appetite Hepatobiliary disorders
Very rare                Hepatitis with or without jaundice
Skin and subcutaneous tissue disorders
Very common              Hyperhidrosis
Common                   Allergic dermatitis (skin rash, urticaria), photosensitivity reaction, pruritus Very rare                Alopecia, purpura
Musculoskeletal and connective tissue disorders
Common                   Muscular weakness, muscle hypertonia
Renal and urinary disorders
Very common              Micturition disorder
Very rare                Urinary retention
Reproductive system and breast disorders
Very common              Erectile dysfunction
Common                   Galactorrhoea, breast enlargement
General disorders and administration site conditions
Very common              Fatigue
Very rare                Hyperpyrexia, oedema (local or generalised)
Investigations
Very common              Weight increased
Common                   Clinically irrelevant ECG changes (e.g., ST and T changes) in patients of normal cardiac status, transaminases increased
Uncommon                 Increased blood pressure
Very rare                Conduction disorder (e.g., widening of QRS complex, prolonged QT interval, PQ changes), electroencephalogram abnormal
Additional adverse drug reactions from post-marketing spontaneous reports The following additional adverse drug reactions have been identified with Anafranil oral or IM/IV dosage forms based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Nervous system disorders
Frequency not known:     serotonin syndrome, extrapyramidal disorder (including akathisia and tardive dyskinesia).

Musculoskeletal and connective tissue disorders
Frequency not known:     rhabdomyolysis (as a complication of neuroleptic malignant syndrome).

Reproductive system and breast disorders
Frequency not known:     ejaculation failure, ejaculation delayed.
Investigations
Frequency not known:       blood prolactin increased.

Class effect
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs or tricyclic antidepressants. The mechanism leading to this risk is unknown.

Withdrawal symptoms
The following symptoms commonly occur after abrupt withdrawal of clomipramine or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, anxiety (see section 4.4).

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


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: /https://sideeffects.health.gov.il.