Adverse reactions : תופעות לוואי

4.8    Undesirable effects

The pregabalin clinical programme involved over 8,900 patients exposed to pregabalin, of whom over 5,600 were in double- blind placebo controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 12% for patients receiving pregabalin and 5% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence.

In table 2 below all adverse reactions, which occurred at an incidence greater than placebo and in more than one patient, are listed by class and frequency (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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The adverse reactions listed may also be associated with the underlying disease and/or concomitant medicinal products.

In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, CNS adverse reactions and especially somnolence was increased (see section 4.4).

Additional reactions reported from postmarketing experience are included in italics in the list below.

Table 2. Pregabalin Adverse Drug Reactions
System Organ Class            Adverse drug reactions
Infections and infestations
Common                        Nasopharyngitis
Blood and lymphatic system disorders
Uncommon                      Neutropaenia
Immune system disorders
Uncommon                      Hypersensitivity
Rare                          Angioedema, allergic reaction
Metabolism and nutrition disorders
Common                             Appetite increased
Uncommon                           Anorexia, hypoglycaemia
Psychiatric disorders
Common                             Euphoric mood, confusion, irritability, disorientation, insomnia, libido decreased Uncommon                           Hallucination, panic attack, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood swings, depersonalisation, word finding difficulty, abnormal dreams, libido increased, anorgasmia, apathy
Rare                               Disinhibition, suicidal behaviour, suicidal ideation Not known                          Drug dependence
Nervous system disorders
Very Common                        Dizziness, somnolence, headache
Common                             Ataxia, coordination abnormal, tremor, dysarthria, amnesia, memory impairment, disturbance in attention, paraesthesia, hypoaesthesia, sedation, balance disorder, lethargy



Uncommon                        Syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, dizziness postural, intention tremor, nystagmus, cognitive disorder, mental impairment, speech disorder, hyporeflexia, hyperaesthesia, burning sensation, ageusia, malaise
Rare                            Convulsions, parosmia, hypokinesia, dysgraphia, parkinsonism 
Eye disorders
Common                          Vision blurred, diplopia
Uncommon                        Peripheral vision loss, visual disturbance, eye swelling, visual field defect, visual acuity reduced, eye pain, asthenopia, photopsia, dry eye, lacrimation increased, eye irritation.
Rare                            Vision loss, keratitis, oscillopsia, altered visual depth perception, mydriasis, strabismus, visual brightness
Ear and labyrinth disorders
Common                          Vertigo
Uncommon                        Hyperacusis
Cardiac disorders
Uncommon                        Tachycardia, atrioventricular block first degree, sinus bradycardia, congestive heart failure
Rare                            QT prolongation, sinus tachycardia, sinus arrhythmia Vascular disorders
Uncommon                        Hypotension, hypertension, hot flushes, flushing, peripheral coldness 
Respiratory, thoracic and mediastinal disorders
Uncommon                       Dyspnoea, epistaxis, cough, nasal congestion, rhinitis, snoring, nasal dryness Rare                           Pulmonary oedema , throat tightness
Not known                      Respiratory depression
Gastrointestinal disorders
Common                         Vomiting, nausea, constipation, diarrhoea, flatulence, abdominal distension, dry mouth
Uncommon                       Gastrooesophageal reflux disease, salivary hypersecretion, hypoaesthesia oral Rare                           Ascites, pancreatitis, swollen tongue, dysphagia Hepatobiliary disorders
Uncommon                       Elevated liver enzymes*
Rare                           Jaundice
Very rare                      Hepatic failure, hepatitis
Skin and subcutaneous tissue disorders
Uncommon                       Rash papular, urticaria, hyperhidrosis, pruritus Rare                           Toxic epidermal necrolysis, Stevens-Johnson syndrome, cold sweat Musculoskeletal and connective tissue disorders
Common                         Muscle cramp, arthralgia, back pain, pain in limb, cervical spasm Uncommon                       Joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness Rare                           Rhabdomyolysis
Renal and urinary disorders
Uncommon                       Urinary incontinence, dysuria
Rare                           Renal failure, oliguria, urinary retention Reproductive system and breast disorders
Common                         Erectile dysfunction
Uncommon                       Sexual dysfunction, ejaculation delayed, dysmenorrhoea, breast pain Rare                           Amenorrhoea, breast discharge, breast enlargement, gynaecomastia General disorders and administration site conditions
Common                         Oedema peripheral, oedema, gait abnormal, fall, feeling drunk, feeling abnormal, fatigue
Uncommon                       Generalised oedema, face oedema, chest tightness, pain, pyrexia, thirst, chills, asthenia
Investigations
     Common                        Weight increased
Uncommon                      Blood creatine phosphokinase increased, blood glucose increased, platelet count decreased, blood creatinine increased, blood potassium decreased, weight decreased Rare                             White blood cell count decreased
* Alanine aminotransferase increased (ALT) and aspartate aminotransferase increased (AST).

After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms have been observed. The following symptoms have been reported: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, suicidal ideation, pain, hyperhidrosis and dizziness. These symptoms may indicate drug dependence.
The patient should be informed about this at the start of the treatment.

Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be dose-related (see sections 4.2 and 4.4).

Paediatric population
The pregabalin safety profile observed in five paediatric studies in patients with partial seizures with or without secondary generalisation (12-week efficacy and safety study in patients 4 to 16 years of age, n=295; 14-day efficacy and safety study in patients 1 month to younger than 4 years of age, n=175; pharmacokinetic and tolerability study, n=65; and two 1 year open label follow on safety studies, n=54 and n=431) was similar to that observed in the adult studies of patients with epilepsy. The most common adverse events observed in the 12-week study with pregabalin treatment were somnolence, pyrexia, upper respiratory tract infection, increased appetite, weight increased, and nasopharyngitis. The most common adverse events observed in the 14-day study with pregabalin treatment were somnolence, upper respiratory tract infection, and pyrexia (see sections 4.2, 5.1 and 5.2).

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/