Neuropathic pain:

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

Epilepsy;

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

Generalized Anxiety Disorder:

Neurogab 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. No data are available.

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.

NEUROGAB 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 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 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. 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 there are no data of the incidence and severity of withdrawal symptoms in relation to duration of use and dose of pregabalin.

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 behavior  have been reported  in patients  treated with anti-epileptic agents in several indications. A meta-analysis of randomized placebo controlled studies of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behavior. The  mechanism  of  this  risk  is  not  known  and  the  available  data  do  not  exclude  the possibility of an increased risk for pregabalin.

Therefore patients should be monitored for signs of suicidal ideation and behaviors and

appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behavior 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 pregabalin was co- administered  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).

Abuse potential

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.

Encephalopathy

Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.

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 are 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.

Lactose intolerance

Neurogab   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.

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.

As the potential risk for humans is unknown, effective contraception must be used in women of

child bearing potential.

Pregnancy

Pregnancy Category C.

There are no adequate data from the use of pregabalin in pregnant women.

Studies in animals have shown reproductive toxicity (see 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 fetus).

Breast-feeding

It is not known if pregabalin is excreted in the breast milk of humans; however, it is present in the  milk  of  rats.  Therefore,  breast-feeding   is  not  recommended   during  treatment  with pregabalin.

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).

Neurogab 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  there  are  no  data  of  the incidence and severity of withdrawal symptoms in relation to duration of use and dose of pregabalin.

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.

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. Inter-subject 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.

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).

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

-            Titanium Dioxide (E171)

Not Applicable.

Store below 30oC.

- Clear PVC/PVDC blister strips and aluminium foil

-  Each unit carton contains 30 capsules.

No special requirements for disposal.