Neuropathic pain:

Pregadex is indicated for the treatment of peripheral and central neuropathic pain in adults.

Epilepsy;

Pregadex is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.

Generalized Anxiety Disorder:

Pregadex is indicated for the treatment of Generalized Anxiety Disorder (GAD) in adults.

The dose range is 150 to 600 mg per day given in either two or three divided doses.

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.

Generalized 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.

Discontinuation of pregabalin

In accordance with current clinical practice, if pregabalin has to be discontinued it is recommended this should be done gradually over a minimum of 1 week independent of the indication (see sections 4.4 and 4.8).

Special populations

Pediatric Use:

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. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Geriatric Use (over 65 years of age):

Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see patients with renal impairment).

Patient with renal impairment:

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. As pregabalin clearance is directly proportional to creatinine clearance (see section 5.2), dose reduction in patients with compromised renal function must be individualized 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:

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.

Use in patients with hepatic impairment

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

Method of administration

Pregabalin may be taken with or without food.

PREGADEX is for oral use only.

Diabetic patients

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

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. In the clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction and visual field changes was greater in pregabalintreated 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 pregabalin 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 of concomitant antiepileptic medicinal products

There are insufficient data for the withdrawal of concomitant antiepileptic medicinal products, once seizure control with pregabalin in the add-on situation has been reached, in order to reach monotherapy on pregabalin.

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, diarrhea, 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 pregabalin, data suggest that the incidence and severity ofwithdrawal symptoms may be dose-related.

Congestive heart failure

There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication. Pregabalin should be used with caution in these patients. Discontinuation of pregabalin may resolve the reaction.

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 medicinal products (e.g. anti-spasticity agents) needed for this condition. This should be considered when prescribing pregabalin in this condition.

Suicidal ideation and behavior

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebocontrolled studies of anti-epileptic drugs has also showna small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known. Cases of suicidal ideation and behaviour have been observed in patients treated with pregabalin in the postmarketingexperience (see section 4.8). An epidemiological study using a self-controlled study design (comparing treatment periods with nontreatment periods within an individual) showed evidence of an increased risk of newonset of suicidal behaviour and death by suicide in patients treated with pregabalin.

Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge. Patients should be monitored for signs of suicidal ideation and behaviour andappropriate treatment should be considered. Discontinuation of pregabalin treatment should be considered in case of suicidal ideation and behaviour.

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 coadministered with medications that have the potential to produce constipation, such as opioid analgesics. When pregabalin and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and elderly).

Misuse, abuse potential or dependence

Cases of abuse have been reported. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of pregabalin abuse.

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 pregabalin 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.

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 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).

Lactose intolerance

Pregadex contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Concomitant use with opioids

Caution is advised when prescribing pregabalin 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 concomitantlywith 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 (≤ 300mg, 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]).

Respiratory Depression

Pregabalin has been associated with serious, life-threatening, and fatal respiratory depression. The risk may be increased with the concomitant use of opioids and other central nervous system (CNS) depressants, and with conditions such as chronic obstructive pulmonary disease. The elderly is also at higher risk. Health care providers should start pregabalin at the lowest dose and monitor patients for symptoms of respiratory depression and sedation when co-prescribing pregabalin with an opioid or other CNS depressants (eg, benzodiazepines). Patients with underlying respiratory disease and elderly patients are also at increased risk and should be managed similarly.

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.

In vivo studies and population pharmacokinetic analysis

Accordingly, in vivo studies no clinically relevant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis indicated that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and/or ethinyl oestradiol

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

Ethanol, lorazepam, oxycodone

Pregabalin 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 post marketing experience, there are reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medicinal products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.

Opioids and CNS depressants

Serious respiratory depression may occur with pregabalin when co-administered with opioids and CNS depressants such as benzodiazepine. Therefore, monitor for symptoms of respiratory depression and sedation in patients who require concomitant treatment with opioids or CNS depressants.

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 have to use effective contraception during treatment (see section 4.4). 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

Studies in animals have shown reproductive toxicity (see section 5.3). Risk related to epilepsy and antiepileptic medicinal products in general Pregabalin has been shown to cross the placenta in rats (see section 5.2). Pregabalin may cross the human placenta.

The risk of birth defects is increased by a factor of 2 – 3 in the offspring of mothers treated with an antiepileptic medicinal product. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practised whenever possible. Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential and the need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child.

Major congenital malformations

Data from a Nordic observational study of more than 2,700 pregnancies exposed to pregabalin in the first trimester showed a higher prevalence of major congenital malformations (MCM) among the paediatricpopulation (live or stillborn) exposed to pregabalin compared to the unexposed population (5.9% vs. 4.1%).

Risk related to pregabalin

The risk of MCM among the paediatric population exposed to pregabalin in the first trimester was slightly higher compared to unexposed population (adjusted prevalence ratio and 95% confidence interval: 1.14 (0.96-1.35)) and compared to population exposed to lamotrigine (1.29 (1.01–1.65)) or to duloxetine (1.39 (1.07–1.82)).

There is a limited amount of data from the use of pregabalin in pregnant women. A population-based cohort study of 2,712 pregabalin exposed pregnancies indicates a slightly increased risk of major congenital malformations associated with the use of pregabalin in pregnancy. However, this study was subject to some limitations and further data are needed to reach a definitive conclusion.

The analyses on specific malformations showed higher risks for malformations of the nervous system, the eye, orofacial clefts, urinary malformations and genital malformations, but numbers were small and estimatesimprecise. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Pregabalin should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus).

Breast-feeding

Pregabalin is excreted into human milk (see section 5.2). The effect of pregabalin on newborns/infants is unknown. A decision must be made whether to discontinue breastfeeding or to discontinue pregabalin therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

There are no clinical data on the effects of pregabalin on female fertility. In a clinical trial to assess the effect of pregabalin on sperm motility, healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment, there were no effects on sperm motility. A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats have shown adverse reproductive and developmental effects. The clinical relevance of these findings is unknown (see section 5.3).

Pregadex may have minor or moderate influence on the ability to drive and use machines. Pregabalin may cause dizziness and somnolence and therefore may influence the ability to drive or use 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.

The pregabalin clinical programme involved over 8900 patients who were exposed to pregabalin, of whom over 5600 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 the table 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. In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, CNS adverse reactions and especially somnolence was increased (See 4.4). Additional reactions reported from post-marketing experience are included as Frequency not known in italics in the list below.

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, diarrhea, flu syndrome, convulsions, nervousness, depression, pain, hyperhidrosis and dizziness. 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.

Paediatric population

The pregabalin safety profile observed in five paediatric studies in patients with partial seizures with or without secondary generalization (12-week efficacy and safety study in patients 4 to 16 years of age , n=295; 14-day efficacy and safety study in patients 1month to younger than 4years of age, n=175; pharmacokinetic and tolerability study, n=65; and two 1 year open label follow on safety studies, n=54 and n=431) was similar tothat observed in the adult studies of patients with epilepsy. The most common adverse events observed in the 12-week study with pregabalin treatment were somnolence, pyrexia, upper respiratory tract infection, increased appetite, weight increased, and nasopharyngitis. The most common adverse events observed in the 14- day study with pregabalin treatment were somnolence, upper respiratory tract infection, and pyrexia (see sections 4.2, 5.1 and 5.2).

In overdoses up to 15 g, no unexpected adverse reactions were reported. 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.

Treatment of pregabalin overdose should include general supportive measures and may include haemodialysis if necessary (see section 4.2 Table 1).

- Anatomical Therapeutical Chemical (ATC):

N03AX16.

- Pharmacotherapeutic group:

The active substance, pregabalin, is a gamma-aminobutyric acid analogue ((S)-3- (aminomethyl)-5- methylhexanoic acid).

Mechanism of action

Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system, potently displacing [3H]-gabapentin.

Clinical experience

Neuropathic pain

Efficacy has been shown in trials in diabetic neuropathy, post herpetic neuralgia and spinal cord injury. Efficacy has not been studied in other models of neuropathic pain. Pregabalin has been studied in 10 controlled clinical trials of up to 13 weeks with twice a day dosing (BID) and up to 8 weeks with three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and TID dosing regimens were similar.

In clinical trials up to 12 weeks for both peripheral and central neuropathic pain, a reduction in pain was seen by week 1 and was maintained throughout the treatment period. In controlled clinical trials in peripheral neuropathic pain 35% of the pregabalin treated patients and 18% of the patients on placebo had a 50% improvement in pain score. For patient’s not experiencing somnolence, such an improvement was observed in 33% of patients treated with pregabalin and 18% of patients on placebo. For patients who experienced somnolence the responder rates were 48% on pregabalin and 16% on placebo. In the controlled clinical trial in central neuropathic pain 22% of the Pregabalin treated patients and 7% of the patients on placebo had a 50% improvement in pain score.

Epilepsy

Pregabalin has been studied in 3 controlled clinical trials of 12 week duration with either twice a day dosing (BID) or three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and TID dosing regimens were similar. A reduction in seizure frequency was observed by Week 1.

Paediatric population

The efficacy and safety of pregabalin as adjunctive treatment for epilepsy in paediatric patients below the age of 12 and adolescents has not been established. The adverse events observed in a pharmacokinetic andtolerability study that enrolled patients from 3 months to 16 years of age (n=65) with partial onset seizures were similar to those observed in adults. Results of a 12-week placebo-controlled study of 295 paediatricpatients aged 4 to 16 years and a 14-day placebo-controlled study of 175 paediatric patients aged 1 month to younger than 4 years of age performed to evaluate the efficacy and safety of pregabalin as adjunctivetherapy for the treatment of partial onset seizures and two 1 year open label safety studies in 54 and 431 paediatric patients respectively, from 3 months to 16 years of age with epilepsy indicate that the adverseevents of pyrexia and upper respiratory infections were observed more frequently than in adult studies of patients with epilepsy (see sections 4.2, 4.8 and 5.2).

In the 12-week placebo-controlled study (4 to 16 years of age), paediatric patients were assigned to pregabalin 2.5 mg/kg/day (maximum, 150 mg/day), pregabalin 10 mg/kg/day (maximum, 600 mg/day), or placebo.The percentage of subjects with at least a 50% reduction in partial onset seizures as compared to baseline was 40.6% of subjects treated with pregabalin 10 mg/kg/day (p=0.0068 versus placebo), 29.1% of subjectstreated with pregabalin 2.5 mg/kg/day (p=0.2600 versus placebo) and 22.6% of those receiving placebo.

In the 14-day placebo-controlled study, paediatric patients (1 month to younger than 4 years of age) were assigned to pregabalin 7 mg/kg/day, pregabalin 14 mg/kg/day, or placebo. Median 24-hour seizurefrequencies at baseline and at the final visit were 4.7 and 3.8 for pregabalin 7 mg/kg/day, 5.4 and 1.4 for pregabalin 14 mg/kg/day, and 2.9 and 2.3 for placebo, respectively. Pregabalin 14 mg/kg/day significantlyreduced the log-transformed partial onset seizure frequency versus placebo (p=0.0223); pregabalin 7 mg/kg/day did not show improvement relative to placebo.

In a 12-week placebo-controlled study in subjects with Primary Generalized TonicClonic (PGTC) seizures 219 subjects (aged 5 to 65 years, of which 66 were aged 5 to 16 years) were assigned to pregabalin 5mg/kg/day (maximum 300 mg/day), 10 mg/kg/day (maximum 600 mg/day) or placebo as adjunctive therapy. The percentage of subjects with at least a 50% reduction in PGTC seizure rate was 41.3%, 38.9% and41.7% for pregabalin 5 mg/kg/day, pregabalin 10 mg/kg/day and placebo respectively. Monotherapy (newly diagnosed patients)

Pregabalin has been studied in 1 controlled clinical trial of 56 week duration with BID dosing. Pregabalin did not achieve non-inferiority to lamotrigine based on the 6-month seizure freedom endpoint. Pregabalin andlamotrigine were similarly safe and well tolerated.

Generalized Anxiety Disorder

Pregabalin has been studied in 6 controlled trials of 4-6 week duration, an elderly study of 8 week duration and a long-term relapse prevention study with a double blind relapse prevention phase of 6 months duration. Relief of the symptoms of GAD as reflected by the Hamilton Anxiety Rating Scale (HAM-A) was observed by Week 1.

In controlled clinical trials (4-8 week duration) 52% of the pregabalin treated patients and 38% of the patients on placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint. 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. Ophthalmologic testing (including visual acuity testing, formal visual field testing and dilated funduscopic examination) was conducted in over 3600 patients within controlled clinical trials. In these patients, visual acuity was reduced in 6.5% of patients treated with pregabalin, and 4.8% of placebo-treated patients. Visual field changes were detected in 12.4% of pregabalin-treated, and 11.7% of placebo-treated patients. Funduscopic changes were observed in 1.7% of pregabalin-treated and 2.1% of placebo-treated patients.

Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy receiving anti-epileptic drugs and patients with chronic pain.

Absorption

Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within 1 hour following both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥90% and is independent of dose. Following repeated administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by approximately 25-30% and a delay in tmax to approximately 2.5 hours. However, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin absorption.

Distribution

In preclinical studies, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the apparent volume of distribution of pregabalin following oral administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins.

Biotransformation

Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin, approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, there was no indication of racemisation of pregabalin S-enantiomer to the Renantiomer.

Elimination

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance (see section 5.2 Renal impairment). Dose adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see Section 4.2 Table 1).

Linearity / non-linearity

Pregabalin pharmacokinetics are linear over the recommended daily dose range. Intersubject pharmacokinetic variability for pregabalin is low (<20%). Multiple dose pharmacokinetics are predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.

Pharmacokinetic properties in Special Populations

Gender

Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of pregabalin.

Renal impairment

Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by haemodialysis (following a 4 hour haemodialysis treatment plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is the major elimination pathway, dose reduction in patients with renal impairment and dose supplementation following haemodialysis is necessary (see section 4.2 Table 1).

Hepatic impairment

No specific pharmacokinetic studies were carried out in patients with impaired liver function. Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.

Paediatric population

Pregabalin pharmacokinetics were evaluated in paediatric patients with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years and 12 to 16 years) at dose levels of 2.5, 5, 10 and 15 mg/kg/day in apharmacokinetic and tolerability study.

Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decreases in creatinine clearance associated with increasing age. Reduction of pregabalin dose may be required in patients who have age related compromised renal function (see section 4.2 Table 1).

After oral administration of pregabalin in paediatric patients in the fasted state, in general, time to reach peak plasma concentration was similar across the entire age group and occurred 0.5 hours to 2 hours postdose.

Pregabalin Cmax and AUC parameters increased in a linear manner with increasing dose within each age group. The AUC was lower by 30% in paediatric patients below a weight of 30 kg due to an increased bodyweight adjusted clearance of 43% for these patients in comparison to patients weighing ≥30 kg.

Pregabalin terminal half-life averaged about 3 to 4 hours in paediatric patients up to 6 years of age, and 4 to 6 hours in those 7 years of age and older.

Population pharmacokinetic analysis showed that creatinine clearance was a significant covariate of pregabalin oral clearance, body weight was a significant covariate of pregabalin apparent oral volume ofdistribution, and these relationships were similar in paediatric and adult patients. Pregabalin pharmacokinetics in patients younger than 3 months old have not been studied (see sections 4.2, 4.8 and 5.1).

Elderly (over 65 years of age)

Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decreases in creatinine clearance associated with increasing age. Reduction of pregabalin dose may be required in patients who have age related compromised renal function (see section 4.2 Table 1).

Breast-feeding mothers

The pharmacokinetics of 150 mg pregabalin given every 12 hours (300 mg daily dose) was evaluated in 10 lactating women who were at least 12 weeks postpartum. Lactation had little to no influence on pregabalinpharmacokinetics. Pregabalin was excreted into breast milk with average steady-state concentrations approximately 76% of those in maternal plasma. The estimated infant dose from breast milk (assuming mean milkconsumption of 150 mL/kg/day) of women receiving 300 mg/day or the maximum dose of 600 mg/day would be 0.31 or 0.62 mg/kg/day, respectively. These estimated doses are approximately 7% of the total dailymaternal dose on a mg/kg basis.

In conventional safety pharmacology studies in animals, pregabalin was well-tolerated at clinically relevant doses. In repeated dose toxicity studies in rats and monkeys CNS effects were observed, including hypoactivity, hyperactivity and ataxia. An increased incidence of retinal atrophy commonly observed in aged albino rats was seen after long term exposure to pregabalin at exposures ≥5 times the mean human exposure at the maximum recommended clinical dose. Pregabalin was not teratogenic in mice, rats or rabbits. Fetal toxicity in rats and rabbits occurred only at exposures sufficiently above human exposure. In prenatal/postnatal toxicity studies, pregabalin induced offspring developmental toxicity in rats at exposures>2 times the maximum recommended human exposure. Adverse effects on fertility in male and female rats were only observed at exposures sufficiently in excess of therapeutic exposure.

Adverse effects on male reproductive organs and sperm parameters were reversible and occurred only at exposures sufficiently in excess of therapeutic exposure or were associated with spontaneous degenerative processes in male reproductive organs in the rat. Therefore the effects were considered of little or no clinical relevance.

Pregabalin is not genotoxic based on results of a battery of in vitro and in vivo tests. Two-year carcinogenicity studies with pregabalin were conducted in rats and mice. No tumours were observed in rats at exposures up to 24 times the mean human exposure at the maximum recommended clinical dose of 600 mg/day. In mice, no increased incidence of tumours was found at exposures similar to the mean human exposure, but an increased incidence of haemangiosarcoma was observed at higher exposures. The nongenotoxic mechanism of pregabalin-induced tumor formation in mice involves platelet changes and associated endothelial cell proliferation. These platelet changes were not present in rats or in humans based on short term and limited long term clinical data. There is no evidence to suggest an associated risk to humans. In juvenile rats the types of toxicity do not differ qualitatively from those observed in adult rats. However, juvenile rats are more sensitive. At therapeutic exposures, there was evidence of CNS clinical signs of hyperactivity and bruxism and some changes in growth (transient body weight gain suppression). Effects on the estrus cycle were observed at 5-fold the human therapeutic exposure. Reduced acoustic startle response was observed in juvenile rats 1-2 weeks after exposure at>2 times the human therapeutic exposure. Nine weeks after exposure, this effect was no longer observable.

Excipients

- Lactose NF Fast Flow.

- Starch (1500).

- Purified Talc.

Capsule Shell (Body and Cap) Contains of

- Gelatin

Not Applicable.

−Store below 30oC.

--Clear PVC/PVDC blister strips and aluminium foil

- Each unit carton contains 30 capsules.

No special requirements for disposal.