Adverse reactions : תופעות לוואי

4.8     Undesirable effects

The safety of topiramate was evaluated from a clinical trial database consisting of 4,111 patients (3,182 on topiramate and 929 on placebo) who participated in 20 double-blind trials and 2,847 patients who participated in 34 open-label trials, respectively, for topiramate as adjunctive treatment of primary generalised tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, monotherapy for newly or recently diagnosed epilepsy or migraine prophylaxis. The majority of adverse reactions were mild to moderate in severity. Adverse reactions identified in clinical trials, and during post-marketing experience (as indicated by “*”) are listed by their incidence in clinical trials in Table 1. Assigned frequencies are as follows:

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
Not known             cannot be estimated from the available data

The most common adverse reactions (those with an incidence of >5% and greater than that observed in placebo in at least 1 indication in double-blind controlled studies with topiramate) include: anorexia, decreased appetite, bradyphrenia, depression, expressive language disorder, insomnia, coordination abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia, hypoaesthesia, lethargy, memory impairment, nystagmus, paraesthesia, somnolence, tremor, diplopia, vision blurred, diarrhoea, nausea, fatigue, irritability, and weight decreased.

Table 1: Topiramate Adverse Reactions
System Organ          Very common         Common             Uncommon          Rare                     Not known Class
Infections and        nasopharyngitis* infestations
Blood and                                 anaemia                 leucopenia,      neutropenia* lymphatic system                                                  thrombocytopenia disorders                                                         lymphadenopathy, eosinophilia
Immune system                             hypersensitivity                                              allergic disorders                                                                                               oedema* Metabolism and                            anorexia, decreased metabolic acidosis,   acidosis nutrition disorders                       appetite            hypokalaemia,         hyperchloraemic, increased appetite,   hyperammonaemia*,
polydipsia            hyperammonaemic encephalopathy*



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Psychiatric   depression     bradyphrenia,          suicidal ideation, mania, panic disorders                    insomnia,              suicide attempt,       disorder, feeling of expressive             hallucination,         despair*, hypomania language disorder,     psychotic disorder,
anxiety,               hallucination confusional state,     auditory,
disorientation,        hallucination aggression, mood       visual, apathy, lack altered, agitation,    of spontaneous mood swings,           speech, sleep depressed mood,        disorder, affect anger, abnormal        lability, libido behaviour              decreased,
restlessness,
crying, dysphemia,
euphoric mood,
paranoia,
perseveration,
panic attack,
tearfulness, reading disorder, initial insomnia, flat affect, thinking abnormal, loss of libido, listless,
middle insomnia,
distractibility, early morning awakening, panic reaction, elevated mood



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Nervous system       paraesthesia,     disturbance in            depressed level of     apraxia, circadian disorders            somnolence,       attention, memory         consciousness,         rhythm sleep dizziness         impairment,               grand mal              disorder, amnesia, cognitive        convulsion, visual     hyperaesthesia,
disorder, mental          field defect,          hyposmia, anosmia,
impairment,               complex partial        essential tremor,
psychomotor skills        seizures, speech       akinesia,
impaired,                 disorder,              unresponsive to convulsion,               psychomotor            stimuli coordination              hyperactivity,
abnormal, tremor,         syncope, sensory lethargy,                 disturbance,
hypoaesthesia,            drooling,
nystagmus,                hypersomnia,
dysgeusia, balance        aphasia, repetitive disorder,                 speech,
dysarthria,               hypokinesia,
intention tremor,         dyskinesia,
sedation                  dizziness postural,
poor quality sleep,
burning sensation,
sensory loss,
parosmia,
cerebellar syndrome,
dysaesthesia,
hypogeusia, stupor,
clumsiness, aura,
ageusia,
dysgraphia,
dysphasia,
neuropathy peripheral,
presyncope,
dystonia,
formication
Eye disorders                          vision blurred,           visual acuity          blindness unilateral,   angle closure diplopia, visual          reduced, scotoma,      blindness transient,    glaucoma*, disturbance               myopia*, abnormal      glaucoma,               maculopathy*, sensation in eye*,     accommodation           eye movement dry eye,               disorder, altered       disorder*,
photophobia,           visual depth            conjunctival blepharospasm,         perception,             oedema*,
lacrimation            scintillating           uveitis increased,             scotoma, eyelid photopsia,             oedema*, night mydriasis,             blindness,
presbyopia             amblyopia
Ear and labyrinth                      vertigo, tinnitus,        deafness, deafness disorders                              ear pain                  unilateral, deafness neurosensory, ear discomfort, hearing impaired
Cardiac disorders                                                bradycardia, sinus bradycardia,
palpitations
Vascular disorders                                               hypotension,           Raynaud's orthostatic            phenomenon hypotension,
flushing, hot flush


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Respiratory,                            dyspnoea,            dyspnoea thoracic and                            epistaxis, nasal     exertional, mediastinal                             congestion,          paranasal sinus disorders                               rhinorrhoea,         hypersecretion, cough*               dysphonia
Gastrointestinal      nausea, diarrhoea vomiting,            pancreatitis, disorders                               constipation,        flatulence, abdominal pain       gastrooesophageal upper, dyspepsia, reflux disease,
abdominal pain,      abdominal pain dry mouth, stomach lower,
discomfort,          hypoaesthesia oral,
paraesthesia oral, gingival bleeding,
gastritis, abdominal abdominal discomfort           distension,
epigastric discomfort,
abdominal tenderness, salivary hypersecretion, oral pain, breath odour,
glossodynia
Hepatobiliary                                                                          hepatitis, hepatic disorders                                                                              failure 
Skin and                                 alopecia, rash,        anhidrosis,            Stevens-Johnson      toxic epidermal subcutaneous tissue                      pruritus               hypoaesthesia          syndrome* erythema necrolysis* disorders                                                       facial, urticaria,     multiforme*, skin erythema, pruritus     odour abnormal,
generalised, rash      periorbital oedema*,
macular, skin          urticaria localised discolouration,
dermatitis allergic,
swelling face
Musculoskeletal                          arthralgia, muscle     joint swelling*,       limb discomfort* and connective                           spasms, myalgia,       musculoskeletal tissue disorders                         muscle twitching,      stiffness, flank muscular               pain, muscle weakness,              fatigue musculoskeletal chest pain
Renal and urinary                        nephrolithiasis,     calculus urinary,        calculus ureteric, disorders                                pollakiuria,         urinary                  renal tubular dysuria,             incontinence,            acidosis* nephrocalcinosis*    haematuria,
incontinence,
micturition urgency, renal colic, renal pain
Reproductive                                                  erectile system and breast                                             dysfunction, sexual disorders                                                     dysfunction General disorders fatigue                pyrexia, asthenia, hyperthermia,              face oedema and administration                       irritability, gait   thirst, influenza site conditions                          disturbance, feeling like illness*, abnormal, malaise sluggishness,
peripheral coldness, feeling drunk, feeling jittery


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Investigations            weight decreased weight increased* crystal urine       blood bicarbonate present, tandem     decreased gait test abnormal,
white blood cell count decreased,
Increase in liver enzymes
Social                                                       learning disability circumstances
*     identified as an adverse reaction from postmarketing spontaneous reports. Its frequency was calculated based on the incidence in clinical trials, or was calculated if the event did not occur in clinical trials.


Congenital malformations and foetal growth restrictions (see section 4.4 and section 4.6).
Paediatric population
Adverse reactions reported more frequently (≥2-fold) in children than in adults in double-blind controlled studies include:
•     Decreased appetite
•     Increased appetite
•     Hyperchloraemic acidosis
•     Hypokalaemia
•     Abnormal behaviour
•     Aggression
•     Apathy
•     Initial insomnia
•     Suicidal ideation
•     Disturbance in attention
•     Lethargy
•     Circadian rhythm sleep disorder
•     Poor quality sleep
•     Lacrimation increased
•     Sinus bradycardia
•     Feeling abnormal
•     Gait disturbance.

Adverse reactions that were reported in children but not in adults in double-blind controlled studies include:
•     Eosinophilia
•     Psychomotor hyperactivity
•     Vertigo
•     Vomiting
•     Hyperthermia
•     Pyrexia
•     Learning disability.

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. suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://sideeffects.health.gov.il