Neuprog 25/75/150 25 mg/ 75 mg /150 mg Capsule

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

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

Special Populations

Renal impairment

NEUPROG is eliminated from the systemic circulation primarily by renal excretion as unchanged medicine. As NEUPROG clearance is directly proportional to creatinine clearance (see section 5.2), 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:

CLcr (mL/min) = (140 u2013 age) x Wt (kg) / 0,82 x Serum creatinine (u03bcmol/L) *For females multiply the CLcr by 0,85

NEUPROG is removed effectively from plasma by haemodialysis (50% of medicine in 4 hours). For patients receiving haemodialysis, the NEUPROG 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. NEUPROG dosage adjustment based on renal function

Creatinine clearance (CLcr) (mL/min)

Total NEUPROG daily dose*

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+

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

Hepatic impairment

No dose adjustment is required for patients with hepatic impairment (see section 5.2).

Elderly

No dosage adjustment is necessary for elderly patients unless their renal function is compromised, see Table 1.

Paediatric population

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

Method of administration

NEUPROG may be taken with or without food. NEUPROG is for oral use only.

Hypersensitivity to the pregabalin or to any of the excipients listed in section 6.1.

Diabetic patients

In accordance with current clinical practice, some diabetic patients who gain weight on NEUPROG treatment may need to adjust hypoglycaemic medicines.

Hypersensitivity reactions

There have been reports in the postmarketing experience of hypersensitivity reactions, including cases of angioedema. NEUPROG should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur (see section 4.8).

Dizziness, somnolence, loss of consciousness, confusion, and mental impairment

NEUPROG 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 (see section 4.8).

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. 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 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. Discontinuation of NEUPROG may result in resolution or improvement of these visual symptoms.

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 pregabalin has been reported (see section 4.8). Renal failure has occurred.

Withdrawal symptoms

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. Patients should be advised to immediately report any symptoms of depression and or suicidal ideation. Concerning discontinuation of long-term treatment of NEUPROG, data suggest that the incidence and severity of withdrawal symptoms may be dose related.

Congestive heart failure

There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin. NEUPROG should be used in caution in these patients with congestive heart failure.

Treatment of 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 medicines (e.g. anti-spasticity medicines) needed for this condition. This should be considered when prescribing NEUPROG in this condition.

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 pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. When NEUPROG 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 NEUPROG 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 NEUPROG 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 medicine metabolism in vitro, and is not bound to plasma proteins, it is unlikely to produce, or be subject to, pharmacokinetic interactions.

In vivo studies and population pharmacokinetic analysis indicated that the 3 commonly used drug classes, oral antidiabetics, diuretics, insulin, and the commonly used anti-epileptic drugs, phenobarbital, tiagabine and topiramate had no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and/or ethinyl oestradiol

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

Central nervous system influencing medicines

NEUPROG may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, multiple oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. 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 medicines. NEUPROG appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.

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 childbearing potential.

Pregnancy

There are no adequate data from the use of NEUPROG in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. NEUPROG should not be used during pregnancy.

Breast-feeding

It is not known if NEUPROG is excreted in the breast milk of humans; however, it is present in the milk of rats. Therefore, breastfeeding is not recommended. The effect of NEUPROG on newborns/infants is unknown.

Fertility

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

NEUPROG may cause dizziness and somnolence and therefore may influence the ability to drive or operate 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.

Summary of the safety profile

The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in intensity.

Adverse reactions

Below all adverse reactions, which occurred at an incidence greater than placebo and in more than one patient, are listed by class and frequency (frequent, (u22651/10); (u22651 /100 to <1/10); less frequent (u22651/1,000 to <1/100); (u22651/10,000 to <1/1,000); (< 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 medicines. Additional reactions reported from post-marketing experience are included in italics in the list below.

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, depersonalisation, word finding difficulty, abnormal dreams, libido increased, anorgasmia, apathy, disinhibition

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: Vision blurred, diplopia

Less frequent: Peripheral vision loss, visual disturbance, eye swelling, visual field defect, visual acuity reduced, eye pain, asthenopia, photopsia, dry eye, lacrimation increased, 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, atrioventricular block first degree, sinus bradycardia, congestive heart failure, QT prolongation, sinus tachycardia, sinus arrhythmia

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

Gastrointestinal disorders

Frequent: Vomiting, nausea, constipation, diarrhoea, flatulence, abdominal distension, dry mouth

Less frequent: Gastrooesophageal reflux disease, salivary hypersecretion, hypoaesthesia 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, 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, ejaculation delayed, dysmenorrhoea, breast pain, Amenorrhoea, breast discharge, breast enlargement, gynaecomastia

General disorders and administration site conditions

Frequent: Oedema peripheral, oedema, gait abnormal, fall, feeling drunk, feeling abnormal, fatigue

Less frequent: Generalised oedema, face oedema, chest tightness, pain, pyrexia, thirst, chills, asthenia

Investigations

Frequent: Weight increased

Less frequent: Blood creatine phosphokinase increased, blood glucose increased, platelet count decreased, blood creatinine increased, blood potassium decreased, weight decreased, White blood cell count decreased, Alanine aminotransferase increased (ALT) and aspartate aminotransferase increased (AST).

Description of selected adverse reactions

After discontinuation of short-term and long-term treatment with NEUPROG 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.

Symptoms

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, and restlessness. Seizures were also reported. In rare occasions, cases of coma have been reported.

Management

Treatment of NEUPROG overdose should include general supportive measures and may include haemodialysis if necessary (see section 4.2).