Adverse reactions : תופעות לוואי

4.8. Undesirable effects

The undesirable effects were categorised based on the following frequency conventions: 
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)
Not known (frequency cannot be estimated from the available data)

There is increasing evidence regarding the association of genetic markers and the occurrence of cutaneous ADRs such as SJS, TEN, DRESS, AGEP and maculopapular rash.
In Japanese and European patients, these reactions have been reported to be associated with the use of carbamazepine and the presence of the HLA-A*3101 allele. Another marker, HLA-B*1502 has been shown to be strongly associated with SJS and TEN among individuals of Han Chinese, Thai and some other Asian ancestry (see sections 4.2 and 4.4 for further information).

The observed undesirable effects occurred less often when carbamazepine was administered alone (monotherapy) than in combination with other antiepileptic agents (combination therapy).
Some of the adverse reactions were dose-dependent, in particular at the start of treatment, if the initial dose is too high or very commonly or commonly in elderly patients. These include central nervous system disorders (dizziness, headache, ataxia, drowsiness, sedation, double vision), gastrointestinal disorders (nausea, vomiting) and allergic skin reactions.
Dose-dependent adverse reactions usually abate within a few days on their own or after a temporary dosage reduction. Therefore, the Timonil retard dosage should titrated if at all possible. Central nervous system disturbances may be a sign of a relative overdose or large fluctuations in the plasma levels, therefore in these cases it is recommended that the plasma levels be checked.

Infections and infestations
Not known:             Reactivation of Human herpesvirus 6 infection.

Blood and lymphatic system disorders
Very common:         Leucopenia. According to the literature, benign leucopenia is the most frequent, transient in about 10% of cases, persistent in 2%.
Benign leucopenia develops mostly during the first four months of therapy. Leucocytosis, thrombocytopenia, eosinophilia.
Rare:                Lymphadenopathy, drop in serum folid acid levels Very rare:           Agranulocytosis, aplastic anaemia, pancytopenia, pure red cell aplasia, anaemia, megaloblastic anaemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda,
reticulocytosis, possibly haemolytic anaemia, enlarged spleen.

Not known:            Bone marrow depression.

Immune system disorders
Uncommon:          A delayed multi-organ hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia,
leucopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (progressive cholestatic hepatopathy with destruction and disappearance of the intrahepatic bile ducts) occurring in various combinations.
Other organs may also be affected (e.g. lungs, kidneys,
pancreas, myocardium, colon).
Very rare:         Aseptic meningitis, with myoclonus and eosinophilia; acute allergic general reactions, anaphylactic reactions, angio-oedema.

Not known:            Allergic cross-reactions with other antiepileptics, reactivation of Herpes virus (might be series when immune system is suppressed.


Endocrine disorders
Common:               Oedema, fluid retention, weight gain, hyponatraemia and blood osmolarity decreased due to an antidiuretic hormone (ADH)-like effect, leading in rare cases to water intoxication accompanied by lethargy, vomiting, headache, confused states, and other neurological disorders.
Very rare:            Elevated prolactin levels with or without clinical manifestations such as galactorrhoea and gynaecomastia, abnormal thyroid function tests: low l-thyroxin (free thyroxine, thyroxine, tri- iodothyronine) and elevated thyroid stimulating hormone in the blood, usually without clinical symptoms, bone metabolism disorders (decrease in serum calcium and 25-hydroxy- cholecalciferol), leading very rarely to osteomalacia or osteoporosis; high cholesterol, including HDL cholesterol and triglycerides, elevated serum free cortisol levels.
There are indications of reduced vitamin B 12 levels and raised serum homocysteine levels.

Psychiatric disorders
Uncommon:             In elderly patients, states of confusion and restlessness (agitation)
Rare:                 Hallucinations (auditory or visual), depression, depressive or manic moods, anorexia, restlessness, aggressive behaviour,
other mental changes.
Very rare:            Activation of latent psychosis, mood changes such as phobic disorders, impaired thought processes, lack of drive.

Nervous system disorders
Very common:        Dizziness, ataxia (atactic and cerebellar dysfunctions), somnolence, sedation, drowsiness, fatigue.
Common:             Headache, diplopia, accommodation disorders (e.g. blurred vision).
Uncommon:           Involuntary movements (e.g. tremor, asterixis, dystonia, tics); eye movement disturbances, including nystagmus.
Rare:               Dyskinetic disturbances such as orofacial dyskinesia, choreoathetosis (involuntary movements in the orofacial region such as grimaces, contorted movements), speech disorders (e.g.
dysarthria or slurred speech), polyneuropathy, peripheral neuritis,

                       peripheral neuropathy, paraesthesia, paresis.
Very rare:             Taste disturbances, neuroleptic malignant syndrome.
Not known:             Memory impairment, memory loss, drowsiness.
There are indications that carbamazepine can lead to exacerbation of the symptoms of multiple sclerosis. Like other antiepileptics seizures may occur more frequently under carbamazepine; absences in particular may be aggravated or may be developed.
Cases of aseptic meningitis have been reported under carbamazepine therapy.

Eye disorders
Very rare:            Cataracts, conjunctivitis, elevated intraocular pressure. Reports have been received of retinotoxicity in two patients on long-term carbamazepine therapy; this resolved after discontinuing carbamazepine.

Ear and labyrinth disorders
Very rare:            Hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception.

Cardiac disorders
Uncommon:             Cardiac conduction disorders, atrioventricular block in isolated cases with syncope, hypertension or hypotension.
Uncommon to rare:     Bradycardia, arrhythmia, circulatory collapse, heart failure, aggravation of coronary artery disease, thrombophlebitis,
thrombo-embolism (e.g. pulmonary embolism).

Respiratory, thoracic and mediastinal disorders
Very rare:            Pulmonary hypersensitivity with fever, dyspnoea, and pneumonitis or pneumonia (alveolitis), single cases of pulmonary fibrosis have been described in the literature.

Gastrointestinal disorders
Very common :         Nausea, vomiting.
Common:               Loss of appetite, dry mouth
Uncommon:             Diarrhoea, constipation.
Rare:                 Abdominal pain.
Very rare:            Inflammation of the oral and pharyngeal mucosa (stomatitis, gingivitis, glossitis), pancreatitis.
Not known:            Colitis, diarrhea, abdominal pain, fever (signs to inflammatory bowl disease).

Hepatobiliary disorders
Very common:          Increased-gamma-GT values (due to hepatic enzyme induction), usually not clinically relevant.
Common:               Increased blood alkaline phosphatase.
Uncommon:             Increased transaminases.
Rare:                 Various forms of hepatitis (cholestatic, hepatocellular, or mixed type), vanishing bile duct syndrome, jaundice, acute life- threatening hepatitis, particularly during the first months of therapy, hepatic failure.
Very rare:            Granulomatous liver disease.

Skin and subcutaneous tissue disorders:
Very common:        Allergic skin reactions with and without fever, such as urticaria, which may be severe.
Uncommon:           Exfoliative dermatitis, erythroderma.
Rare:               Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (see section 4.4), Systemic lupus

                       erythematosus, pruritus.
Very rare:            Photosensitivity, erythema multiforme exudativum and erythema nodosum, alterations in skin pigmentation, purpura, acne,
hyperhydrosis, alopecia, hirsutism, and vasculitis have been reported very rarely, but the causal relationship is unclear.
Not known:            Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), acute generalised exanthematic pustulosis (AGEP),
lichenoid keratosis, onychomadesis, vitiligo, purple or re-purple swelling that may be itchy.

Musculoskeletal and connective tissue disorders
Rare:                Muscle weakness.
Very rare:           Arthralgia, muscle pain, muscle spasms.
Not known:           Fractures, fall out of the nails, bone fractures, decrease in bone density.

Renal and urinary disorders
Uncommon:            Renal impairment (e.g. albuminuria, haematuria, oliguria, elevated blood urea/azotaemia).
Very rare:           Tubulointerstitial nephritis, renal failure, other urinary comlaints (e.g. urinary frequency, dysuria, pollakisuria, urinary retention).

Reproductive system and breast disorders
Very rare:          Sexual dysfunction, reduced libido, erectile dysfunction, reduced male fertility and/or abnormal spermatogenesis (low sperm count and/or motility).

Investigations
Very rare:            Hypogammaglobulinaemia.

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with carbamazepine. The mechanism by which carbamazepine affects bone metabolism has not been identified.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic @moh.gov.il