Nubacap 25, 75, 150 25mg, 75mg, 150mg CAPSULES

NUBACAP is indicated for the treatment of adult patients with neuropathic pain due to Herpes zoster infections and diabetes.

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

Special Populations

Patients with renal impairment: NUBACAP is eliminated from the systemic circulation primarily by renal excretion as unchanged medicine. As NUBACAP clearance is directly proportional to creatinine clearance (see section 5.2, Special patient groups, Renal impairment), dosage reduction in patients with compromised renal function must be individualised according to creatinine clearance (CLcr), as indicated in Table 1 and determined using the following formula: CLcr (mL/min) = (140 u2013 age) x Wt (kg) / (0.82 x serum creatinine (u03bcmol/L)) *For females multiply the CLcr by 0.85. NUBACAP is removed effectively from plasma by haemodialysis (50% of NUBACAP in 4 hours). For patients receiving haemodialysis, the NUBACAP 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: NUBACAP dosage adjustment based on renal function

Creatinine clearance (CLcr) (mL/min) Total NUBACAP daily dose* Dose regimen Starting dose (mg/day) Maximum dose (mg/day) u2265 60 150 300 Two divided doses 30 - 60 75 150 Once daily or Two divided doses 15 - 30 25 - 50 75 Once daily or Two divided doses < 15 25 25 - 50 Once daily Supplementary dosage following haemodialysis (mg) 25 50 Single dose + *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. + Supplementary dose is a single additional dose.

Patients with hepatic impairment: No dosage adjustment is required for patients with hepatic impairment (see section 5.2, Special patient groups, Hepatic impairment).

Elderly patients (over 65 years of age): No dosage adjustment is necessary for elderly patients unless their renal function is compromised (see Table 1).

Paediatric population: The safety and effectiveness of NUBACAP in patients below the age of 18 years, with neuropathic pain, have not been established.

Method of administration NUBACAP is given orally with or without food.

Hypersensitivity to pregabalin or to any of the inactive ingredients of NUBACAP (see sections 2 and 6.1).

Hypersensitivity reactions: There have been post-marketing reports of hypersensitivity reactions, including cases of angioedema and urticaria. NUBACAP should be discontinued immediately if symptoms of angioedema, such as facial, perioral or upper airway swelling occur (see section 4.8).

Severe cutaneous adverse reactions (SCARs): 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 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, NUBACAP should be withdrawn immediately and an alternative treatment considered (as appropriate).

Diabetic patients: NUBACAP may increase weight gain. Diabetic patients who gain weight on NUBACAP treatment may need to adjust the dose of hypoglycaemic medicines.

Congestive heart failure: There have been post-marketing reports of congestive heart failure or deterioration of heart failure in some patients receiving NUBACAP. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral oedema and cardiovascular complications such as hypertension or congestive heart failure. NUBACAP should be used with caution in patients with congestive heart failure (see section 4.8).

Renal failure: Although the effects of discontinuation on the reversibility of renal failure have not been systematically studied, improved renal function following discontinuation or dose reduction of NUBACAP has been reported (see section 4.8). Renal failure has occurred.

Dizziness, somnolence, loss of consciousness and mental impairment: NUBACAP treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in elderly patients. There have 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 NUBACAP (see section 4.8).

Antidepressants: When NUBACAP is used in combination with antidepressants, respiratory failure has occurred.

Withdrawal symptoms: After discontinuation of short-term and long-term treatment with NUBACAP, withdrawal symptoms have been observed in some patients. The following events have been mentioned: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, nervousness, depression, pain, convulsions, hyperhidrosis and dizziness, suggestive of physical dependence (see section 4.8). Patients should be informed about this at the start of the treatment.

Convulsions, including status epilepticus and grand mal convulsions, may occur during NUBACAP use or shortly after discontinuing NUBACAP. Concerning discontinuation of long-term treatment of NUBACAP, data suggest that the incidence and severity of withdrawal symptoms may be dose-related.

Vision-related effects: There have been post-marketing reports of visual adverse reactions including loss of vision, visual blurring or other changes of visual acuity, many of which were transient. Discontinuation of NUBACAP may result in resolution or improvement of these visual symptoms.

Additional adverse effects found in patients with central neuropathic pain due to spinal cord injury: 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 medicines) needed for this condition. This should be considered when prescribing pregabalin in this condition.

Suicidal ideation and behaviour: Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicines in several indications. 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.

Reduced lower gastrointestinal tract function: There are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g. intestinal obstruction, paralytic ileus, constipation) when NUBACAP was co-administered with medicines that have the potential to produce constipation, such as opioid analgesics. When NUBACAP and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and the elderly).

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 NUBACAP misuse, abuse or dependence (development of tolerance, dose escalation, substance-seeking behaviour have been reported).

Encephalopathy: Cases of encephalopathy have 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 NUBACAP 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).

Since NUBACAP is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (< 2% of a dose recovered in urine as metabolites), does not inhibit substance metabolism in vitro, and is not bound to plasma proteins, NUBACAP is unlikely to produce, or be subject to, pharmacokinetic interactions. Accordingly, in vivo studies indicated no clinically relevant pharmacokinetic interactions between NUBACAP 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 NUBACAP had no clinically significant effect on the clearance of phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate and phenobarbitone. Co-administration of NUBACAP with the oral contraceptives norethisterone and/or ethinylestradiol does not influence the steady-state pharmacokinetics of either medicine. Multiple oral doses of NUBACAP co-administered with oxycodone, lorazepam or ethanol did not result in clinically important effects on respiration. NUBACAP appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. NUBACAP may potentiate the effects of ethanol and lorazepam. In post-marketing experience, there are reports of respiratory failure and coma in patients taking NUBACAP and other central nervous system (CNS) depressant medicines.

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

Lactation: It is not known if NUBACAP is excreted into the breast milk of humans; however, it is present in the milk of rats. Therefore, breastfeeding is not recommended.

NUBACAP frequently causes dizziness and somnolence (see section 4.8). Caution is advised before driving a vehicle or operating machinery until it is established that the ability to perform such activities is not affected.

System Organ Class Frequency Side effects Infections and infestations Less frequent Infection, nasopharyngitis. Blood and the lymphatic system disorders Less frequent Neutropenia. Immune system disorders Less frequent Hypersensitivity reaction, Stevens-Johnson syndrome, angioedema, allergic reaction. Metabolism and nutrition disorders Frequent Less frequent Increased appetite. Anorexia, hypoglycaemia. Psychiatric disorders Frequent Less frequent Euphoric mood, confusion, irritability, disorientation, insomnia. Depersonalisation, anorgasmia, restlessness, depression, agitation, mood swings, depressed mood, aggression, word finding difficulty, hallucinations, abnormal dreams, panic attack, apathy, disinhibition, elevated mood, nervousness. Nervous system disorders Frequent Less frequent Dizziness, somnolence, headache, ataxia, attention disorder, abnormal coordination, memory impairment, tremor, dysarthria, paraesthesia, abnormal thinking, amnesia, sedation, balance disorder, lethargy. Cognitive disorder, hypoesthesia, speech disorder, myoclonus, hyporeflexia, dyskinesia, psychomotor hyperactivity, postural dizziness, hyperaesthesia, ageusia, burning sensation, intention tremor, stupor, syncope, loss of consciousness, mental impairment, reversible paralysis, malaise, convulsions, hypokinesia, parosmia, dysgraphia, myasthenia, neuropathy. Eye disorders Frequent Less frequent Blurred vision, diplopia. Visual disturbance, dry eye, eye swelling, visual acuity reduced, eye pain, asthenopia, increased lacrimation, photopsia, eye irritation, mydriasis, vision loss, keratitis, oscillopsia, altered visual depth perception, peripheral vision loss, strabismus, visual brightness, visual field defect, nystagmus. Ear and labyrinth disorders Frequent Less frequent Vertigo. Hyperacusis. Cardiac disorders Less frequent Tachycardia, first degree atrioventricular block, sinus tachycardia, sinus dysrhythmia, sinus bradycardia, congestive heart failure, chest tightness, chest pain, QT prolongation. Vascular disorders Less frequent Flushing, hot flushes, hypotension, peripheral coldness, hypertension. Respiratory, thoracic and mediastinal disorders Less frequent Frequency unknown Dyspnoea, nasal dryness, nasopharyngitis, cough, nasal congestion, epistaxis, rhinitis, snoring, throat tightness, flu symptoms, bronchitis, pulmonary oedema. Respiratory depression Gastrointestinal disorders Frequent Less frequent Dry mouth, constipation, vomiting, flatulence, nausea, diarrhoea, abdominal distension. Salivary hypersecretion, gastro-oesophageal reflux disease, oral hypoesthesia, ascites, dysphagia, pancreatitis, swollen tongue. Hepatobiliary disorders Less frequent Elevated liver enzymes, jaundice, hepatic failure, hepatitis. Skin and subcutaneous tissue disorders Less frequent Sweating, papular rash, cold sweat, urticaria, hyperhidrosis, pruritus. Musculoskeletal, connective tissue and bone disorders Less frequent Muscle twitching, joint swelling, muscle cramp, myalgia, arthralgia, back pain, pain in limb, muscle stiffness, cervical spasm, neck pain, rhabdomyolysis. Renal and urinary disorders Less frequent Dysuria, urinary incontinence, oliguria, renal failure, urinary retention. Reproductive system and breast disorders Frequent Less frequent Erectile dysfunction, decreased libido. Delayed ejaculation, sexual dysfunction, increased libido, amenorrhoea, breast pain, breast discharge, dysmenorrhoea, breast hypertrophy, gynaecomastia. General disorders and administrative site conditions Frequent Less frequent Fatigue, peripheral oedema, facial oedema, oedema, abnormal gait, accidental injury. Asthenia, fall, thirst, exacerbated pain, anasarca, pyrexia, rigors. Investigations Frequent Less frequent Increased weight. Increased alanine aminotransferase, increased blood creatine phosphokinase, increased aspartate aminotransferase, decreased platelet count, increased blood glucose, increased blood creatinine, decreased blood potassium, decreased weight, decreased white blood cell count.

Symptoms: The most commonly reported adverse events observed when NUBACAP was taken in overdose included affective disorder, somnolence, confusion, depression, agitation, restlessness, seizures and coma.

Treatment: Treatment of NUBACAP overdose should be symptomatic and supportive and may include haemodialysis if necessary (see section 4.2, Patients with renal impairment).