Adverse reactions : תופעות לוואי

4.8   Undesirable effects
Assessment of frequency of undesirable effects is based on the following categories: 
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)

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Rare: myelodysplastic syndrome.
Blood and lymphatic system disorders
Common: anaemia, thrombocytopenia (see section 4.4) or leucopenia, which often regresses if treatment continues, but always regresses when valproic acid is withdrawn.
Uncommon: pancytopenia.
Rare: bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis, lymphopenia, neutropenia.

Endocrine disorders
Uncommon: syndrome of inappropriate secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia and/or androgen increased).
Rare: hypothyroidism.

Metabolism and nutrition disorders
Very common: hyperammonaemia (see section 4.4).
Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, but do not require treatment discontinuation. However, cases have also been reported in which neurological symptoms occur. In such cases, further investigations should be considered (see sections 4.3 and 4.4 ”Urea cycle disorders and risk of hyperammonaemia“ and ”Patients at risk of hypocarnitinaemia”).
Common: weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4). or - weight decrease, increased appetite or also loss of appetite, hyponatraemia.
Rare: obesity.
Not known: hypocarnitinaemia (see sections 4.3 and 4.4).

Psychiatric disorders
Common: confusional state, hallucinations, aggression*, agitation*, disturbance in attention*.
Uncommon: irritability, hyperactivity.
Rare: abnormal behaviour*, psychomotor hyperactivity*, learning disorder*.

*These adverse events are principally observed in the paediatric population.
Nervous system disorders
Very common: tremor.
Common: extrapyramidal disorder (may be irreversible), stupor*, somnolence, paraesthesia, convulsion*, memory impairment, headache, nystagmus and dizziness.
Uncommon: coma*, encephalopathy*, lethargy* (see below), reversible parkinsonism, spasticity, ataxia, aggravated convulsions (see section 4.4).
There have been uncommon reports of encephalopathy shortly after the use of medicinal products containing valproic acid. Its pathogenesis has not been clarified and it is reversible after withdrawal of the medicinal product. In some of these cases, there were reports of elevated ammonia levels and, in patients receiving combination treatment with phenobarbital, of a rise in the phenobarbital level.
Rare: Diplopia. Reversible dementia associated with reversible cerebral atrophy, cognitive disorder.
Rarely and especially with high doses or in combination with other anti-epileptics, chronic encephalopathy with neurological symptoms and disorders of higher cortical functions have also been reported. The pathogenesis has also not been clarified adequately.
Frequency not known: sedation.

*Cases of stupor and lethargy sometimes leading to transient coma/encephalopathy have been reported; they were in part associated with an increase in the occurrence of convulsions and their symptoms 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 doses.

During long-term treatment with a combination of Depalept Chrono and other anti-epileptics, particularly phenytoin, signs of brain damage (encephalopathy) may be seen: an increase in seizures, listlessness, stupor, muscle weakness (poor muscle tone) and severe general changes in EEG.

Ear and labyrinth disorders
Common: reversible or irreversible hearing loss.
Frequency not known: tinnitus.

Vascular disorders
Common: haemorrhage (see sections 4.4 and 4.6).
Uncommon: vasculitis.
Respiratory, thoracic and mediastinal disorders
Uncommon: pleural effusion.

Gastrointestinal disorders
Very common: nausea.
Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, diarrhoea, particularly at the start of treatment, upper abdominal pain, which usually regress after a few days despite continuation of the treatment.
Uncommon: pancreatic damage, in some cases with a fatal outcome (see section 4.4), hypersalivation (particularly at the start of treatment).

Hepatobiliary disorders
Common: Serious (sometimes fatal) non-dose-dependent liver injuries. The risk of liver damage is significantly higher in children, particularly those taking other anti-epileptics concomitantly (see section 4.4).

Skin and subcutaneous tissue disorders
Common: hypersensitivity, transient and/or dose related alopecia, nail and nail bed disorders.
Uncommon: angioedema, rash, hair disorder (such as hair texture abnormal, hair colour changes, hair growth abnormal).
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome.

Musculoskeletal and connective tissue disorders
There have been reports of decreased bone mineral density like osteoporosis as well as pathological fractures in patients on long-term therapy with valproic acid. The mechanism by which valproic acid affects bone metabolism has not been identified.
Rare: systemic lupus erythematosus, rhabdomyolysis (see section 4.4).

Renal and urinary disorders
Common: urinary incontinence.
Uncommon: renal failure.
Rare: enuresis, tubulointerstitial nephritis, Fanconi syndrome.

Reproductive system and breast disorders
Common: dysmenorrhoea.
Uncommon: amenorrhoea.
Rare: male infertility (see section 4.6), elevated testosterone levels and polycystic ovaries.
Congenital, familial and genetic disorders
Congenital malformations and developmental disorders (see sections 4.4 and 4.6).

General disorders and administration site conditions
Uncommon: hypothermia, non-severe peripheral oedema.

Investigations
Rare: Valproic acid can reduce the concentration of at least one coagulation factor and inhibit the secondary phase of platelet aggregation, resulting in a prolonged bleeding time.
This may result in abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged, see sections 4.4 and 4.6).
Biotin/biotinidase deficiency may occur.
Not known: acquired Pelger–Huet anomaly.
Acquired Pelger-Huet anomaly has been reported in cases with and without myelodysplastic syndrome.

Paediatric population
The safety profile of valproate in the paediatric population is comparable to adults, but some adverse drug 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 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/