Adverse reactions : תופעות לוואי

4.8.    Undesirable effects

Frequency categories are defined using the following convention:
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 (cannot be estimated from the available data)
Congenital, familial and genetic disorders
Congenital malformations and developmental disorders (see section 4.4 and section 4.6).


Neoplasms benign, malignant and unspecified (including cysts and polyps) Rare:                myelodysplastic syndrome

Hepato-biliary disorders
Common:                 liver injury (see section 4.4); increased liver enzymes, particularly early in treatment, and may be transient (see section 4.4)
Not known:              severe liver damage, including hepatic failure sometimes resulting in fatalities (see sections 4.2, 4.3 and 4.4)

Gastro-intestinal disorders
Very common:            nausea, occurs a few minutes after intravenous injection with spontaneous resolution within a few minutes
Common:                 vomiting, gingival disorder, (mainly gingival hyperplasia), stomatitis gastralgia, diarrhoea These frequently occur at the start of the treatment, but usually disappearing after a few days without discontinuing treatment.
Uncommon:               pancreatitis, sometimes lethal (see section 4.4) Psychiatric disorders
Common:                 confusional state, hallucinations, aggression*, agitation*, disturbance in attention* Rare:                   abnormal behaviour*, psychomotor hyperactivity*, learning disorder* 
*These ADRs are principally observed in the paediatric population.

Nervous system disorders:
Very common:         tremor
Common:              extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus, dizziness may occur a few minutes after intravenous injection; it disappears spontaneously within a few minutes.
Uncommon:            coma*, encephalopathy, lethargy* (see below), reversible parkinsonism, ataxia, paresthesia, aggravated convulsions (see section 4.4)
Rare:                reversible dementia associated with reversible cerebral atrophy, cognitive disorder 
Sedation has been reported occasionally, usually when in combination with other anticonvulsants. In monotherapy it occurred early in treatment on rare occasions and is usually transient.
*Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have uncommonly been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of other anticonvulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.
An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
Endocrine disorders
Uncommon:               Syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increased)
Rare:                   hypothyroidism (see section 4.6)

Metabolism and nutrition disorders
Common:                hyponatraemia, weight increased*
*Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4).
Rare:                   hyperammonaemia* (see section 4.4), obesity

*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur Orfiril injection should be discontinued.
Hyperammonaemia associated with neurological symptoms has also been reported. In such cases further investigations should be considered (see sections 4.3 and 4.4).
Not known:              hypocarnitinaemia (see section 4.3 and 4.4)
Blood and lymphatic system disorders
Common:               anaemia, thrombocytopenia (see section 4.4)
Uncommon:             pancytopenia, leucopenia

Rare:                   bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis.
The blood picture returned to normal when the drug was discontinued.

Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (Orfiril injection has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see also section 4.6).).
Skin and subcutaneous tissue disorders
Common:              hypersensitivity, transient and/or dose related alopecia (hair loss). Regrowth normally begins within 6 months, although the hair may become more curly than previously.
nail and nail bed disorders
Uncommon:            angioedema, rash, hair disorder (such as abnormal hair texture, hair colour changes, abnormal hair growth)
Rare:                toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.
Reproductive system and breast disorders
Common:              dysmenorrhea
Uncommon:            amenorrhea
Rare:                male infertility, polycystic ovaries
Very rare:           gynaecomastia
Vascular disorders
Common:                 haemorrhage (see section 4.4. and 4.6)
Uncommon:               Vasculitis

Eye disorders
Rare:                   diplopia

Ear and labyrinth disorders
Common:                 deafness, a cause and effect relationship has not been established 
Renal and urinary disorders
Common:                urinary incontinence
Uncommon:              renal failure
Rare:                  enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with Orfiril injection therapy, but the mode of action is as yet unclear 
General disorders and administration site conditions
Uncommon:             hypothermia, non-severe oedema peripheral

Musculoskeletal and connective tissue disorders
Uncommon:             bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long- term therapy with Orfiril injection. The mechanism by which Orfiril injection affects bone metabolism has not been identified.
Rare:                   systemic lupus erythematosus (see section 4.4), rhabdomyolysis (see section 4.4) 
Respiratory, thoracic and mediastinal disorders
Uncommon:               pleural effusion
Investigations
Rare:                   coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged).
Paediatric population
The safety profile of valproate in the paediatric population is comparable to adults, but some ADRs 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. Based on a limited number of Post-marketing cases, Fanconi Syndrome, enuresis and gingival hyperplasia have been reported more frequently in paediatric patients than in adult patients.
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.