Neuralyn 25, 50, 75, 100 and 150 mg Capsules, hard

NEURALYN capsules are indicated for the treatment of adult patients with neuropathic pain due to Herpes zoster infections and diabetes.

Posology: The recommended starting dose for NEURALYN 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 NEURALYN has to be discontinued, it is recommended this should be done gradually over a minimum of 1 week.

Special Populations

Patients with renal impairment: NEURALYN is eliminated from the systemic circulation primarily by renal excretion as unchanged pregabalin. As NEURALYN clearance is directly proportional to creatinine clearance (see section 5.2), 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:

Table 1: NEURALYN dosage adjustment based on renal function (1) Creatinine clearance (CLCR) (ml/min) Starting dose (mg/day) Maximum dose (mg/day) u2265 60 150 300 BD 30 - 60 75 150 OD or BD 15 - 30 25 - 50 75 OD or BD < 15 25 25 - 50 OD Supplementary dosage following haemodialysis (mg) 25 50 Single dose' 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 NEURALYN is removed effectively from plasma by haemodialysis (50 % of medicine in 4 hours). For patients receiving haemodialysis, the NEURALYN 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).

Use in patients with hepatic impairment: No dosage adjustment is required for patients with hepatic impairment (see section 5.2).

Paediatric patients: The safety and effectiveness of NEURALYN in patients below the age of 18 years with neuropathic pain has not been established.

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 NEURALYN is given orally with or without food.

Known hypersensitivity to pregabalin or to any of the excipients of NEURALYN (see section 6.1).

Diabetic patients Diabetic patients who gain weight on NEURALYN treatment may need to adjust hypoglycaemic medicines.

Hypersensitivity reactions NEURALYN 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 NEURALYN treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have been reports of loss of consciousness, confusion and mental impairment. Patients should be advised to exercise caution until they are familiar with the potential effects of NEURALYN.

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 NEURALYN may result in resolution or improvement of these visual symptoms.

Renal failure Renal failure has been reported and discontinuation of pregabalin, as in NEURALYN, did show reversibility of this adverse reaction.

Withdrawal symptoms After discontinuation of short - term and long - term treatment with pregabalin, as in NEURALYN, withdrawal symptoms have been observed. 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 NEURALYN use or shortly after discontinuing. Discontinuation of long - term treatment of pregabalin, as in NEURALYN, data suggest that the incidence and severity of withdrawal symptoms may be dose related.

Congestive heart failure Congestive heart failure has been reported. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication. NEURALYN should be used with caution in these patients. Discontinuation of NEURALYN may resolve the reaction.

Suicidal ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with gabapentinoids such as pregabalin in NEURALYN in several indications. Therefore, patients should be monitored for signs of suicidal ideation and behaviours 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 Reduced lower gastrointestinal tract function (e.g. intestinal obstruction, paralytic ileus, constipation) has been reported when pregabalin was co - administered with medicines that have the potential to produce constipation, such as opioid analgesics. When NEURALYN and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and the elderly).

Concomitant use with opioids Caution is advised when prescribing pregabalin concomitantly with opioids due to risk of respiratory depression and 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. This increased risk was observed at low doses of pregabalin (u2264 300 mg) and there was a trend for a greater risk at high doses of pregabalin (> 300 mg).

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 NEURALYN misuse, abuse or dependence (development of tolerance, dose escalation, intentional overdose, drug - seeking behaviour have been reported).

Encephalopathy Encephalopathy has been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.

Respiratory depression 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 opioids, 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).

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 medicine metabolism in vitro, and is not bound to plasma proteins, NEURALYN is unlikely to produce, or be subject to, pharmacokinetic interactions. In vivo studies and population pharmacokinetic analysis Accordingly, in in vivo studies no clinically relevant pharmacokinetic interactions were observed between NEURALYN 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 NEURALYN had no clinically significant effect on the clearance of phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate and phenobarbitone.

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

Central nervous system influencing medicines Multiple oral doses of NEURALYN co - administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. NEURALYN appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. NEURALYN may potentiate the effects of ethanol and lorazepam. In the post marketing experience, there are reports of respiratory failure and coma in patients taking NEURALYN and other CNS depressant medications.

Interactions and the elderly No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.

Women of child - bearing potential/ contraception in males and females As potential risk for humans is unknown, effective contraception must be used in women of child - bearing potential.

Pregnancy There are no adequate data on the use of NEURALYN in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk to humans is unknown. Therefore, NEURALYN should not be used during pregnancy.

Breast - feeding Pregabalin is excreted into human milk (see section 5.2). The effect of pregabalin on new - borns/infants is unknown. Therefore, breastfeeding is not recommended during treatment with NEURALYN.

Fertility There are no clinical data on the effects of pregabalin on female fertility. A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats have shown adverse reproductive and development effects.

NEURALYN frequently causes dizziness and somnolence. Head and body injuries and road traffic incidents have also been reported with pregabalin, as contained in NEURALYN. 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.

a) Summary of adverse effects The most frequently reported adverse reactions were dizziness and somnolence. The most frequent adverse reactions resulting in discontinuation from pregabalin treatment are dizziness and somnolence. In the table below the adverse reactions are listed by system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Additional reactions reported from post marketing experience are also included and listed according to frequency.

b) Tabulated summary of adverse reactions MedDRA system organ class Frequency Adverse reactions Infections and infestations: Frequent Nasopharyngitis Blood and the lymphatic system disorders Less frequent Neutropenia Immune system disorders Less frequent Hypersensitivity, angioedema, allergic reaction Metabolism and nutrition disorders Frequent Increased appetite Less frequent Anorexia, hypoglycaemia Psychiatric disorders Frequent Euphoric mood, confusion, irritability, disorientation, insomnia, decreased libido Less frequent Hallucination, panic attack, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood swings, depersonalisation, word finding difficulty, abnormal dreams, increased libido, anorgasmia, apathy, disinhibition Unknown frequency Suicidal ideation and behaviour Nervous system disorders Frequent Dizziness, somnolence, headache, ataxia, coordination abnormal, tremor, dysarthria, amnesia, memory impairment, disturbance in attention, paraesthesia, hypoaesthesia, 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, hyporeflexia, hyperaesthesia, burning sensation, ageusia, malaise, convulsions, parosmia, hypokinesia, dysgraphia Eye disorders Frequent Blurred vision, diplopia Less frequent Peripheral vision loss, visual disturbance, eye swelling, visual field defect, reduced visual acuity, eye pain, asthenopia, photopsia, dry eye, increased lacrimation, eye irritation, vision loss, keratitis, oscillopsia, altered visual depth perception, mydriasis, strabismus, visual brightness Ear and labyrinth disorders Frequent Vertigo Less frequent Hyperacusis Cardiac disorders Less frequent Tachycardia, first degree atrioventricular block, sinus bradycardia, congestive heart failure, QT prolongation, sinus tachycardia, sinus dysrhythmia Vascular disorders Less frequent Hypotension, hypertension, hot flushes, flushing, peripheral coldness Respiratory, thoracic and mediastinal disorders: Less frequent Dyspnoea, epistaxis, cough, nasal congestion, rhinitis, snoring, nasal dryness, pulmonary oedema, throat tightness Frequency not known Respiratory depression Gastrointestinal disorders: Frequent Vomiting, nausea, constipation, diarrhoea, flatulence, abdominal distension, dry mouth Less frequent Gastro - oesophageal reflux disease, salivary hypersecretion, oral hypoaesthesia, ascites, pancreatitis, swollen tongue, dysphagia Hepatobiliary disorders Less frequent Elevated liver enzymes*, jaundice, hepatic failure, hepatitis Skin and subcutaneous tissue disorders: Less frequent Papular rash, urticaria, hyperhidrosis, pruritus, Stevens - Johnson syndrome, cold sweat Musculoskeletal and connective tissue disorders: Frequent Muscle cramp, arthralgia, back pain, pain in limb, cervical spasm Less frequent Joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness, 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, delayed ejaculation, dysmenorrhoea, breast pain, amenorrhoea, breast discharge, breast enlargement, gynaecomastia General disorders and administration site conditions: Frequent Peripheral oedema, oedema, abnormal gait, fall, feeling drunk, feeling abnormal, fatigue Less frequent Generalised oedema, face oedema, chest tightness, pain, pyrexia, thirst, chills, asthenia Investigations: Frequent Increased weight (2) Less frequent Increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, decreased weight, decreased white blood cell count * Alanine aminotransferase increased (ALT) and aspartate aminotransferase increased (AST).

c. Description of selected adverse reactions 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.

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who - umc.org) found on SAHPRA website. Side effects must also be reported to Unicorn Pharmaceuticals (Pty) Ltd to [email protected].

In the post marketing experience, the most commonly reported adverse reactions observed when pregabalin was taken in overdose included affective disorder, somnolence, confusional state, agitation, depression 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).