Nergil 25mg. 75 mg. 150 mg CAPSULE

Neuropathic Pain: NERGIL is indicated for the treatment of neuropathic pain due to Herpes zoster infections and diabetes in adult patients.

Posology The recommended starting dose for NERGIL is 75 mg twice daily (150 mg/day), with or without food. Based on individual patient response and tolerability, the dose may be increased to 150 mg twice daily after an interval of 3 to 7 days. In accordance with current clinical practice, if NERGIL has to be discontinued, it is recommended this should be done gradually over a minimum of 1 week. Patients with renal impairment: NERGIL is eliminated from the systemic circulation primarily by renal excretion as unchanged pregabalin. As NERGIL clearance is directly proportional to creatinine clearance (see section 5.2 u2013 Renal impairment), dosage 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: CLcr (mL/min) = (140 u2013 age) x Weight (kg) 0,82 x serum creatinine (u03bcmol/L) * For females multiply the CLcr by 0,85

NERGIL is removed effectively from plasma by haemodialysis (50 % of drug in 4 hours). For patients receiving haemodialysis, the NERGIL 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 BD = Two divided doses OD = Once daily * Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. + Supplementary dose is a single additional dose. Use in patients with hepatic impairment: No dosage adjustment is required for patients with hepatic impairment (see section 5.2 u2013 Hepatic impairment). The safety and effectiveness of NERGIL in patients below the age of 18 years with neuropathic pain has not been established. Creatinine Clearance (CLcr) (mL/min) Total NERGIL Daily Dose* Dose Regimen Starting dose (mg/day) Maximum dose (mg/day) u2265 60 150 300 BD 30 u2013 60 75 150 OD or BD 15 u2013 30 25 u2013 50 75 OD or BD < 15 25 25 u2013 50 OD Supplementary dosage following haemodialysis (mg) 25 50 Single dose+

Use in the elderly (over 65 years of age): No dosage adjustment is necessary for elderly patients unless their renal function is compromised, see Table 1. Method of administration NERGIL is given orally with or without food

NERGIL is contraindicated in patients who are hypersensitive to the active ingredient pregabalin or to any of excipients listed in 6.1

Diabetic patients Diabetic patients who gain weight on NERGIL treatment may need to adjust hypoglycaemic medicinal products. Hypersensitivity reactions There have been reports 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. 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 Visual adverse reactions have been reported, including loss of vision, visual blurring or other changes of visual acuity, many of which were transient. Discontinuation of NERGIL may result in resolution or improvement of these visual symptoms. Renal failure Cases of renal failure have been reported and in some cases discontinuation of pregabalin did show reversibility of this adverse reaction. Withdrawal symptoms After discontinuation of short-term and long-term treatment with pregabalin, as contained in NERGIL, 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 NERGIL , data suggest that the incidence and severity of withdrawal symptoms may be dose-related. Congestive heart failure Congestive heart failure have been reported in some patients receiving pregabalin. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication. NERGIL should be used with caution in these patients. Discontinuation of NERGIL may resolve the reaction.

Suicidal ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with gabapentinoids, such as pregabalin in NERGIL , in several indications. Therefore, patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients and caregivers should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge. Reduced lower gastrointestinal tract function Events related to reduced lower gastrointestinal tract function (e.g. intestinal obstruction, paralytic ileus, constipation) have been reported when pregabalin as contained in NERGIL , was co-administered with medicines that have the potential to produce constipation, such as opioid analgesics. When NERGIL and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and elderly).

Concomitant use with opioids Caution is advised when prescribing NERGIL 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 ( u2264 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]).

Misuse, abuse potential or dependence 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 NERGIL misuse, abuse or dependence (development of tolerance, dose escalation, drug- seeking behaviour have been reported). Encephalopathy Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.

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 NERGIL and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. In addition, population pharmacokinetic analysis indicated that the 3 commonly used medicine classes, oral antidiabetics, diuretics and insulin, and the commonly used anti-epileptic medicines, phenytoin, carbamazepine, valproic acid, lamotrigine, phenobarbitone, tiagabine, and topiramate, had no clinically significant effect on pregabalin clearance. Similarly, these analyses indicated that NERGIL had no clinically significant effect on the clearance of phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate and phenobarbitone.

Co-administration of NERGIL with the oral contraceptives norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either medicine.

Multiple oral doses of NERGIL co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. NERGIL appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. NERGIL may potentiate the effects of ethanol and lorazepam. There are reports of respiratory failure and coma in patients taking NERGIL and other central nervous system depressant medicines. Interactions and the elderly No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.

Women of childbearing potential/Contraception in males and females As the potential risk for humans is unknown, effective contraception must be used in women of child bearing potential. Pregnancy There are no adequate data from the use of pregabalin in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. NERGIL should not be used during pregnancy. Breastfeeding Pregabalin is excreted into human milk. The effect of pregabalin on newborns/infants is unknown. Therefore, breastfeeding is not recommended during treatment with NERGIL .

Fertility There are no clinical data on the effects of pregabalin on female fertility.

NERGIL frequently causes dizziness and somnolence. Head and body injuries and road traffic incidents have also been reported with pregabalin as contained in NERGIL Therefore, patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicine affects their ability to perform these activities.

Some cases of hypersensitivity reactions (including angioedema) have been reported with NERGIL. The most common adverse effects associated with NERGIL are dizziness, somnolence, loss of consciousness, confusion and mental impairment, with the elderly population the most prone to these adverse effects. Visual adverse reactions (loss of vision and visual blurring) have also been reported but these symptoms have been known to resolve or improve upon discontinuing treatment with NERGIL (see section 4.4). The most commonly reported adverse reactions are tabulated below. The frequencies are defined as follows: Frequent u2261 more frequentu2019, Less frequent u2261 u2018single reportsu2019, u2018isolated reportsu2019, or not frequent u2018 u201cFrequency not knownu201d or u201cfrequency unknownu201d When no frequency data are available for a specific ADR, the statement added, with justification provided in the cover letter for the lack of information and providing the reference sources consulted.

Tabulated list of adverse reactions System Organ Class Adverse drug reactions Infections and infestations Frequent Nasopharyngitis Blood and lymphatic system disorders Less frequent Neutropenia Immune system disorders Less frequent Hypersensitivity Angioedema, allergic reaction Metabolism and nutrition disorders Frequent Appetite increased Less frequent Anorexia, hypoglycaemia Psychiatric disorders Frequent Euphoric mood, confusion, irritability, disorientation, insomnia, libido decreased Less frequent Hallucination, panic attack, restlessness, agitation, depression, depressed mood, elevated mood, aggression , mood swings, insomnia, depersonalisation, word finding difficulty, abnormal dreams, libido increased, anorgasmia, apathy, disinhibition, elevated mood Frequency unknown Suicidal ideation and behaviour Nervous system disorders Frequent Dizziness, somnolence, headache, ataxia, coordination abnormal, tremor, dysarthria, amnesia, memory impairment, disturbance in attention, paraesthesia, hypaesthesia, sedation, balance disorder, lethargy

Less frequent Syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, dizziness postural, intention tremor, nystagmus, cognitive disorder, mental impairment, speech disorder, visual field defect, hyporeflexia, hyperaesthesia, burning sensation, ageusia, malaise, convulsions, parosmia, hypokinesia, dysgraphia Eye disorders Frequent Vision blurred, diplopia Less frequent visual disturbance, eye swelling, visual field defect, visual acuity reduced, eye pain, asthenopia, dry eye, lacrimation increased, eye irritation , photopsia, vision loss, keratitis, oscillopsia, altered visual depth perception, mydriasis, strabismus, visual brightness, peripheral vision loss, Ear and labyrinth disorders Frequent Vertigo Less frequent Hyperacusis Cardiac disorders Less frequent Tachycardia, congestive heart failure, atrioventricular block first degree, sinus bradycardia , QT prolongation, sinus tachycardia, sinus dysrhythmia Vascular disorders Less frequent Hot flushes, flushing, hypotension, hypertension, peripheral coldness Respiratory, thoracic and mediastinal disorders Less frequent Dyspnoea, nasal dryness epistaxis, nasopharyngitis cough, nasal congestion, rhinitis, snoring, pulmonary oedema, throat tightness Gastrointestinal disorders Frequent Vomiting, nausea , constipation, diarrhoea , flatulence, abdominal distension, dry mouth Less frequent Gastroesophageal reflux disease, salivary hypersecretion, hypaesthesia oral, ascites, pancreatitis, swollen tongue, dysphagia Hepatobiliary disorders Less frequent Elevated liver enzymes, jaundice, hepatic failure, hepatitis Skin and subcutaneous tissue disorders Less frequent Rash papular, sweating, urticaria, hyperhidrosis, pruritus, Stevens Johnson syndrome, cold sweat Musculoskeletal and connective tissue disorders Frequent Muscle cramp, back pain, pain in limb, cervical spasm Less frequent Joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness, arthralgia, rhabdomyolysis Renal and urinary disorders Less frequent Urinary incontinence, dysuria, renal failure, oliguria, urinary retention Reproductive system and breast disorders Frequent Erectile dysfunction Less frequent Sexual dysfunction, ejaculation delayed, dysmenorrhoea, amenorrhoea, breast discharge, breast enlargement, breast pain , gynaecomastia General disorders and administration site conditions Frequent Oedema peripheral, oedema, gait abnormal, feeling drunk, feeling abnormal, fatigue Less frequent Generalised oedema, face oedema, fall, chest tightness, pain, pyrexia, thirst, chills, asthenia Investigations Frequent Weight increased Less frequent Alanine aminotransferase increased, aspartate aminotransferase increased, Blood creatine phosphokinase increased, platelet count decreased, white blood cell count decreased, blood glucose increased, blood creatinine increased, blood potassium decreased, weight decreased Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c 6.04 Adverse Medicine Reactions Reporting Form u201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

In the post marketing experience, the most commonly reported adverse reactions observed when pregabalin was taken in overdose included somnolence, confusional state, agitation, and restlessness. Seizures were also reported. In rare occasions, cases of coma have been reported. Treatment of pregabalin overdose should include general supportive measures and may include haemodialysis if necessary (see section 4.2 Table 1).