Adverse reactions : תופעות לוואי

4.8       Undesirable effects

Summary of the safety profile
Particularly at the start of treatment with Tegretol, or if the initial dosage is too high, or when treating elderly patients, certain types of adverse reaction occur very commonly or commonly, e.g. CNS adverse reactions (dizziness, headache, ataxia, drowsiness, fatigue, diplopia), gastrointestinal disturbances (nausea, vomiting), and allergic skin reactions.

The dose-related adverse reactions usually abate within a few days, either spontaneously or after a transient dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or significant fluctuation in plasma levels. In such cases it is advisable to monitor plasma levels.
Tabulated summary of adverse drug reactions compiled from clinical trials and from spontaneous reports
Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class.
Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Table 1
Blood and lymphatic system disorders
Very common:       leukopenia
Common:            thrombocytopenia, eosinophilia
Rare:              leukocytosis, lymphadenopathy
Very rare:         agranulocytosis, aplastic anaemia, pancytopenia, aplasia pure red cell, anaemia, anaemia megaloblastic, reticulocytosis, haemolytic anaemia
Immune system disorders
Rare:              a delayed multiorgan hypersensitivity disorder with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia,
leukopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing bile duct syndrome (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:         anaphylactic reaction, angioedema, hypogammaglobulinaemia Endocrine disorders
Common:            oedema, fluid retention, weight increase, 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, confusional state,
neurological disorders
Very rare:        galactorrhoea, gynecomastia
Metabolism and nutrition disorders
Rare:             folate deficiency, decreased appetite, anorexia
Very rare:        porphyria acute (acute intermittent porphyria and variegate porphyria), porphyria non-acute (porphyria cutanea tarda)
Psychiatric disorders
Rare:             hallucinations (visual or auditory), depression, aggression, agitation, restlessness, confusional state
Very rare:        activation of psychosis
Nervous system disorders
Very common:      ataxia, dizziness, somnolence
Common:           diplopia, headache
Uncommon:         abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics); nystagmus
Rare:             orofacial dyskinesia, eye movement disorder, speech disorders (e.g. dysarthria, slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia, paresis
Very rare:        neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia
Eye disorders
Common:           accommodation disorders (e.g. blurred vision)
Very rare:        lenticular opacities, conjunctivitis


Ear and labyrinth disorders
Very rare:          hearing disorders, e.g. tinnitus, hyperacusis, hypoacusis, change in pitch perception
Cardiac disorders
Rare:               cardiac conduction disorders
Very rare:          arrhythmia, atrioventricular block with syncope, bradycardia, , cardiac failure congestive, coronary artery disease aggravated
Vascular disorders
Rare:               hypertension or hypotension
Very rare:          circulatory collapse, embolism (e.g. pulmonary embolism), thrombophlebitis
Respiratory, thoracic and mediastinal disorders
Very rare:          pulmonary hypersensitivity characterized e.g. by fever, dyspnoea, pneumonitis or pneumonia
Gastrointestinal disorders
Very common:        vomiting, nausea
Common:             dry mouth
Uncommon:           diarrhoea, constipation
Rare:               abdominal pain
Very rare:          pancreatitis, glossitis, stomatitis
Hepatobiliary disorders

Rare:             hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, vanishing bile duct syndrome, jaundice
Very rare:         hepatic failure, granulomatous liver disease
Skin and subcutaneous tissue disorders
Very common:       urticaria which may be severe, dermatitis allergic Uncommon:          dermatitis exfoliative and erythroderma
Rare:              systemic lupus erythematosus, pruritus
Very rare:         Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme,
erythemanodosum, pigmentation disorder, purpura, acne,
hyperhydrosis, alopecia, hirsutism
Musculoskeletal, connective tissue and bone disorders
Rare               muscular weakness
Very rare:         bone metabolism disorders (decrease in plasma calcium and blood 25-hydroxy-cholecalciferol)                  leading             to osteomalacia/osteoporosis, arthralgia, myalgia, muscle spasms
Renal and urinary disorders
Very rare:         tubulointerstitial nephritis, renal failure, renal impairment (e.g.
albuminuria,      haematuria,     oliguria,    and   blood    urea increased/azotemia), urinary retention, urinary frequency
Reproductive system
Very rare:         sexual dysfunction/erectile dysfunction, spermatogenesis abnormal (with decreased sperm count and/or motility)
General disorders and administration site conditions
Very common:       fatigue
Investigations

Very common:          gamma-glutamyltransferase increased (due to hepatic enzyme induction), usually not clinically relevant
Common:               blood alkaline phosphatase increased
Uncommon:             transaminases increased
Very rare:            intraocular pressure increased, blood cholesterol increased, high density lipoprotein increased, blood triglycerides increased.
Thyroid function test abnormal: decreased L-Thyroxin (free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone, usually without clinical manifestations, blood prolactin increased
*In some Asian countries also reported as rare. See also Warnings and precautions for use.

"Emergence or worsening of existing depression, suicidal behaviour and suicidal ideation has been reported in patients treated with antiepileptic agents in several indications. The frequency of these events is unknown."
Additional adverse drug reactions from spontaneous reports (frequency not known): The following adverse drug reactions have been derived from post-marketing experience with Tegretol via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Table 2
Infections and infestations:     Reactivation of Human herpesvirus 6 (HHV-6) infection Blood and lymphatic system       Bone marrow failure disorders:
Injury, poisoning and            Fall (associated with Tegretol treatment induced ataxia, procedural complications         dizziness, somnolence, hypotension, confusional state, sedation) (see section 4.4 Special warning and precautions for use).
Nervous system disorders:        Sedation, memory impairment
Gastrointestinal disorders:      Colitis
Immune system disorders:         Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
Skin and subcutaneous            Acute Generalized Exanthematous Pustulosis (AGEP) tissue disorders:                lichenoid keratosis, onychomadesis
Musculoskeletal and              Fracture connective tissue disorders:
Investigations:                  Bone density decreased

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.

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 .

Reporting of suspected adverse reactions
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 https://sideeffects.health.gov.il and to Novartis using the following email address: safetydesk.israel@novartis.com.