Pregabalin Zentiva K.S.

Medicinal product no longer authorised 4 Neuropathic pain Pregabalin treatment can be started at a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval.

Epilepsy Pregabalin treatment can be started with a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week. The maximum dose of 600 mg per day may be achieved after an additional week.

Generalised anxiety disorder The dose range is 150 to 600 mg per day given as two or three divided doses. The need for treatment should be reassessed regularly. Pregabalin treatment can be started with a dose of 150 mg per day. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week.

Following an additional week the dose may be increased to 450 mg per day. The maximum dose of 600 mg per day may be achieved after an additional week. 8). Renal impairment Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.

2), dose reduction in patients with compromised renal function must be individualised according to creatinine clearance (CLcr), as indicated in Table 1 determined using the following formula: Pregabalin is removed effectively from plasma by haemodialysis (50% of drug in 4 hours).

For patients receiving haemodialysis, the pregabalin daily dose should be adjusted based on renal function. In addition to the daily dose, a supplementary dose should be given immediately following every 4 hour haemodialysis treatment (see Table 1).

Table 1. Pregabalin dose adjustment based on renal function Creatinine clearance (CLcr) (ml/min) Total pregabalin daily dose * Dose regimen Starting dose (mg/day) Maximum dose (mg/day) ≥ 60 150 600 BID or TID ≥ 30 – < 60 75 300 BID or TID ≥ 15 – < 30 25 – 50 150 Once daily or BID < 15 25 75 Once daily Supplementary dosage following haemodialysis (mg) 25 100 Single dose + TID = Three divided doses.

BID = Two divided doses. * Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. + Supplementary dose is a single additional dose. 2). 23 × [140 - age (years)] × weight (kg) serum creatinine (μmol/l)Medicinal product no longer authorised 5 Paediatric population The safety and efficacy of pregabalin in children below the age of 12 years and in adolescents (12 – 17 years of age) have not been established.

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. 4). Additional reactions reported from post-marketing 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 ideationMedicinal product no longer authorised 10 System Organ Class Adverse drug reactions 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 spasmMedicinal product no longer authorised 11 System Organ Class Adverse drug reactions 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).

Diabetic patients In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycaemic medicinal products. Hypersensitivity reactions There have been reports in the post-marketing 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. Severe cutaneous adverse reactions (SCARs) 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).

Dizziness, somnolence, loss of consciousness, confusion, and mental impairment 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 post- marketing 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.

Vision-related effects 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. 1). In the post-marketing 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.

1.