Neuropathic pain
Lyrgaba is indicated for the treatment of peripheral and central neuropathic pain in adults.
Epilepsy
Lyrgaba is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.
Generalised anxiety disorder
Lyrgaba is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults

Posology
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.
Generalised 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).
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 individualised according to creatinine clearance (CLcr)

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

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
Hepatic impairment
No dose adjustment is required for patients with hepatic impairment (see section 5.2).
Paediatric population
The safety and efficacy of Lyrgaba 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 sections 4.8, 5.1 and 5.2 but no
recommendation on a posology can be made.
Elderly
Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see section 5.2).
Method of administration
Lyrgaba may be taken with or without food.
Lyrgaba 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 hypoglycaemic medicinal products.
Hypersensitivity reactions
There have been reports in the postmarketing 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 postmarketing 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 postmarketing 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.
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 (e.g. benzodiazepines).
Patients with underlying respiratory disease and elderly patients are also at increased risk and should be
managed similarly.
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 anti-epileptic medicinal products
There are insufficient data for the withdrawal of concomitant anti-epileptic 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,
diarrhoea, flu syndrome, nervousness, depression, pain, convulsion, hyperhidrosis and dizziness, suggestive of
physical dependence. The patient should be informed about this at the start of the treatment.
Convulsions, including status epilepticus and grand mal convulsions, may occur during pregabalin use or shortly
after discontinuing pregabalin.
Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of
withdrawal symptoms may be dose-related.

Congestive heart failure
There have been postmarketing 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 behaviour

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several
indications. A meta-analysis of randomised placebo-controlled studies of anti-epileptic drugs has also shown a
small increased risk of suicidal ideation and behaviour. 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 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 postmarketing 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).
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 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.
Lactose intolerance
Lyrgaba 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 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.
Central nervous system influencing medical products
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 postmarketing experience, there are reports of respiratory failure and coma in patients

taking pregabalin and other central nervous system (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/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 pregabalin in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Lyrgaba 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 new-borns/infants is
unknown. A decision must be made whether to discontinue breast-feeding or to discontinue pregabalin therapy
taking into account the benefit of breast-feeding 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).

Lyrgaba may have minor or moderate influence on the ability to drive and use machines. Lyrgaba 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 8,900 patients exposed to pregabalin, of whom over 5,600 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 table 2 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 section 4.4).

After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms have been
observed in some patients. The following reactions have been mentioned: insomnia, headache, nausea, anxiety,
diarrhoea, flu syndrome, convulsions, nervousness, depression, pain, hyperhidrosis and dizziness, suggestive
of physical dependence. The patient should be informed about this at the start of the treatment.
Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of
withdrawal symptoms may be dose related.
Paediatric population
The pregabalin safety profile observed in four paediatric studies in patients with partial seizures with or without
secondary generalisation (12-week efficacy and safety study in patients 4 to 16 years of age, n=295; 14-day
efficacy and safety study in patients 1 month to younger than 4 years of age, n=175; pharmacokinetic and
tolerability study, n=65; and 1 year open label follow on safety study, n=54) was similar to that 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 the postmarketing experience, the most commonly reported adverse reactions observed when pregabalin was
taken in overdose included somnolence, confusional state, agitation, and restlessness. Seizures were also
reported.
In rare occasions, cases of coma have been reported.
Treatment of pregabalin overdose should include general supportive measures and may include haemodialysis
if necessary

Pharmacotherapeutic group: Anti-epileptics, other anti-epileptics.
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.
Clinical efficacy and safety
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 patients 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
Adjunctive Treatment

Pregabalin has been studied in 3 controlled clinical trials of 12 week duration with either BID or 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 and tolerability
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 paediatric patients 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 adjunctive therapy for the treatment of partial
onset seizures and a 1 year open label safety study in 54 paediatric patients from 3 months to 16 years of age
with epilepsy indicate that the adverse events 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, paediatric patients (4 to 16 years of age) 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 subjects treated 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 seizure frequencies
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 significantly reduced the logtransformed
partial onset seizure frequency versus placebo (p=0.0223); pregabalin 7 mg/kg/day did not show
improvement relative to placebo.
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 and lamotrigine
were similarly safe and well tolerated.
Generalised 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 antiepileptic
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 R-enantiomer.

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.
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 a pharmacokinetic
and tolerability study.
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 body weight
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 of distribution, 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
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 pregabalin
pharmacokinetics. 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
milk consumption 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 daily maternal
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. Foetal 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 hemangiosarcoma was observed at higher exposures. The nongenotoxic
mechanism of pregabalin-induced tumour 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 oestrus 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.

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Store below 30C°.

The immediate packaging material is PVDC/ALU blisters.
Pack size: 30,40 and 60 hard capsules.

Any unused product or waste material should be disposed of in accordance with local requirements.