Source: Υπουργείο Υγείας (CY) Revision Year: 2022 Publisher: Delorbis Pharmaceuticals Ltd., 17 Athinon Street, Ergates Industrial Area, 2643 Ergates, P.O. Box 28629, 2081 Lefkosia, Cyprus, European Union
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported rarely in association with pregabalin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, pregabalin should be withdrawn immediately and an alternative treatment considered (as appropriate).
In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycaemic medicinal products.
There have been reports in the postmarketing experience of hypersensitivity reactions, including cases of angioedema. Pregabalin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.
Pregabalin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have also been postmarketing reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medicinal product.
In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than did patients treated with placebo which resolved in a majority of cases with continued dosing. In the clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction and visual field changes was greater in pregabalin-treated patients than in placebo-treated patients; the incidence of fundoscopic changes was greater in placebo-treated patients (see section 5.1).
In the postmarketing experience, visual adverse reactions have also been reported, including loss of vision, visual blurring or other changes of visual acuity, many of which were transient. Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.
Cases of renal failure have been reported and in some cases discontinuation of pregabalin did show reversibility of this adverse reaction.
There are insufficient data for the withdrawal of concomitant anti-epileptic medicinal products, once seizure control with pregabalin in the add-on situation has been reached, in order to reach monotherapy on pregabalin.
After discontinuation of short-term and long-term treatment with pregabalin, withdrawal symptoms have been observed in some patients. The following events have been mentioned: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, nervousness, depression, pain, convulsion, hyperhidrosis and dizziness, suggestive of physical dependence. The patient should be informed about this at the start of the treatment.
Convulsions, including status epilepticus and grand mal convulsions, may occur during pregabalin use or shortly after discontinuing pregabalin.
Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be dose-related.
There have been postmarketing reports of congestive heart failure in some patients receiving pregabalin. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication. Pregabalin should be used with caution in these patients. Discontinuation of pregabalin may resolve the reaction.
In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, central nervous system adverse reactions and especially somnolence was increased. This may be attributed to an additive effect due to concomitant medicinal products (e.g. anti-spasticity agents) needed for this condition. This should be considered when prescribing pregabalin in this condition.
There have been reports of severe respiratory depression in relation to pregabalin use. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly may be at higher risk of experiencing this severe adverse reaction. Dose adjustments may be necessary in these patients (see section 4.2).
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled studies of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for pregabalin.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
There are postmarketing reports of events related to reduced lower gastrointestinal tract function (e.g. intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. When pregabalin and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and elderly).
Caution is advised when prescribing pregabalin concomitantly with opioids due to risk of CNS depression (see section 4.5). In a case-control study of opioid users, those patients who took pregabalin concomitantly with an opioid had an increased risk for opioid-related death compared to opioid use alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19–2.36]). This increased risk was observed at low doses of pregabalin (≤300 mg, aOR 1.52 [95% CI, 1.04–2.22]) and there was a trend for a greater risk at high doses of pregabalin (>300 mg, aOR 2.51 [95% CI 1.24–5.06]).
Cases of misuse, abuse and dependence have been reported. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of pregabalin misuse, abuse or dependence (development of tolerance, dose escalation, drug-seeking behaviour have been reported).
Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.
Epibal contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), does not inhibit drug metabolism in vitro, and is not bound to plasma proteins, it is unlikely to produce, or be subject to, pharmacokinetic interactions.
Accordingly, in in vivo studies no clinically relevant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis indicated that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on pregabalin clearance.
Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either substance.
Pregabalin may potentiate the effects of ethanol and lorazepam.
In the postmarketing experience, there are reports of respiratory failure, coma and deaths in patients taking pregabalin and opioids and/or other central nervous system (CNS) depressant medicinal products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.
No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.
As the potential risk for humans is unknown, effective contraception must be used in women of child bearing potential.
There are no adequate data from the use of pregabalin in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Epibal should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus).
Pregabalin is excreted into human milk (see section 5.2). The effect of pregabalin on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue pregabalin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
There are no clinical data on the effects of pregabalin on female fertility.
In a clinical trial to assess the effect of pregabalin on sperm motility, healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment, there were no effects on sperm motility.
A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats have shown adverse reproductive and developmental effects. The clinical relevance of these findings is unknown (see section 5.3).
Epibal may have minor or moderate influence on the ability to drive and use machines. Epibal may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform these activities.
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 |
| 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 |
| 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 | Stevens Johnson syndrome, cold sweat, toxic epidermal necrolysis |
| 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 in some patients. The following reactions have been mentioned: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, pain, hyperhidrosis and dizziness, suggestive of physical 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.
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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, www.moh.gov.cy/phs, Tel: +357 22608607, Fax: +357 22608669.
Not applicable.
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