Adverse reactions : תופעות לוואי

4.8.       Undesirable effects
Classification of expected frequencies:
Very common (≥ 10%); common (≥ 1% to < 10%); uncommon (≥ 0.1% to < 1%); rare (≥ 0.01% to < 0.1%); very rare (< 0.01%); not known (cannot be estimated from the available data).
Congenital, familial and genetic disorders
•      Congenital malformations and neuro-developmental disorders (see sections 4.4 and 4.6).
Blood and lymphatic system disorders
•      Common: anemia, thrombocytopenia.
Cases of dose-dependent thrombocytopenia have been reported, generally discovered systematically and without any clinical repercussions.
In patients with asymptomatic thrombocytopenia, if possible, given the platelet level and control of the disease, simply reducing the dose of this medicinal product usually leads to resolution of thrombocytopenia.
•      Uncommon: leukopenia, pancytopenia.
•      Rare: bone marrow aplasia or pure red cell aplasia, agranulocytosis, macrocytic anemia, macrocytosis.
Investigations
•      Common: weight gain*.
•      Rare: decrease in at least 1 coagulation factor, abnormal coagulation tests (such as prolonged prothrombin time, prolonged activated partial thromboplastin time, prolonged thrombin time, prolonged INR) (see sections 4.4 and 4.6), vitamin B8 (biotin) deficiency/biotinidase deficiency.
*as weight gain is a risk factor for polycystic ovary syndrome, patient weight must be carefully monitored (see section 4.4).
Nervous system disorders
•      Very common: tremor
•      Common: extrapyramidal disorders**, stupor*, sedation, seizures*, memory impairment, headache, nystagmus, nausea or dizziness.
•      Uncommon: coma*, encephalopathy*, lethargy*, reversible parkinsonism**, ataxia, paresthesia,
•      Rare: diplopia, cognitive disturbances of insidious and progressive onset (which may progress as far as complete dementia) and which are reversible a few weeks to a few months following treatment withdrawal**
*Cases of stupor and lethargy, sometimes leading to transient coma (encephalopathy), have been observed with valproate; they decreased on withdrawal of treatment or reduction of dosage. These cases mostly occurred during combined therapy (in particular with phenobarbital or topiramate) or after a sudden increase in valproate doses.
**These symptoms can be associated with imaging findings of cerebral atrophy.
Ear and labyrinth disorders
•      Common: hearing loss.
Respiratory, thoracic and mediastinal disorders
•   Uncommon: pleural effusion.
Gastrointestinal disorders
•   Very common: nausea.
•   Common: vomiting, gingival disorders (mainly gingival hyperplasia), stomatitis, upper abdominal pain, diarrhea that may occur in some patients at the start of treatment, but usually disappearing after a few days without discontinuing the treatment.
•   Uncommon: pancreatitis with possibly fatal outcome requiring early treatment discontinuation (see section 4.4).
Renal and urinary disorders
•   Common: urinary incontinence.
•   Uncommon: renal failure.
•   Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome.
Skin and subcutaneous tissue disorders
•   Common: transient and/or dose-related alopecia, nail and nail bed disorders.
•   Uncommon: angioedema, skin reactions, hair disorders (such as abnormal hair texture, hair color changes, abnormal hair growth).
•   Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) or drug hypersensitivity syndrome.
Endocrine disorders
•   Uncommon: inappropriate antidiuretic hormone secretion syndrome (IADHS), hyperandrogenism (hirsutism, virilism, acne, androgenetic alopecia and/or increase in androgen hormone levels).
•   Rare: hypothyroidism (see section 4.6).
Metabolism and nutrition disorders
•   Common: hyponatremia.
•   Rare: hyperammonemia* (see section 4.4), obesity.
*Cases of isolated and moderate hyperammonemia without change in liver function tests may occur, especially during polytherapy, and should not cause treatment discontinuation.
However, cases of hyperammonemia associated with neurological symptoms (which may progress to coma) have also been reported, and require further investigations (see section 4.4).
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
•   Rare: myelodysplastic syndrome.
Vascular disorders
•   Common: hemorrhage (see sections 4.4 and 4.8).
•   Uncommon: cutaneous vasculitis, mainly leukocytoclastic vasculitis.
General disorders and administration site conditions
•   Uncommon: hypothermia, non-severe peripheral edema.
Hepatobiliary disorders
•   Common: liver disorders (see section 4.4).
Reproductive system and breast disorders
•   Common: irregular menstruation.
•   Uncommon: amenorrhea.
•   Rare: male infertility (see section 4.6), polycystic ovaries.
Musculoskeletal and connective tissue disorders
•   Uncommon: decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Depalept. The mechanism of action of Depalept on bone metabolism is not known.
•      Rare: acute systemic lupus erythematosus (see section 4.4), rhabdomyolysis (see section 4.4).
Psychiatric disorders
•      Common: confusional state, hallucinations, aggressiveness*, agitation*, attention disorders*.
•      Rare: abnormal behavior*, psychomotor hyperactivity*, learning disabilities*.
*These effects are mainly observed in the paediatric population.
Paediatric population
The safety profile of valproate in the paediatric population is comparable to adults, but some adverse reactions are more severe or principally observed in the paediatric population. There is a particular risk of severe liver damage in infants and young children especially under the age of 3 years. Young children are also at particular risk of pancreatitis. These risks decrease with increasing age (see section 4.4).
Psychiatric disorders such as aggression, agitation, disturbance in attention, abnormal behaviour, psychomotor hyperactivity and learning disorder are principally observed in the paediatric population.
Reporting of suspected adverse reactions
Reporting suspected adverse events 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/