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

Posology

The dose range is 165 to 660 mg per day given once daily directly after an evening meal.

Treatment with pregabalin prolonged release for neuropathic pain can be started at a dose of 165 mg per day given once daily directly after an evening meal and can be increased to 330 mg given once daily within 1 week based on individual patient response and tolerability. The maximum recommended dose of pregabalin prolonged release is 660 mg once daily, directly after an evening meal.

Advice in case of missed dose

It is important that patient take the tablets regularly at the same time each day. If the patient misses a dose of Misabri PR, the patient should be told to take it as soon as possible and always after some food, unless it is time for the next dose. In that case, the patient should be told not to take the missed dose and simply resume the usual dosing schedule. Patients must not take a double dose to make up for a forgotten dose.

Conversion from pregabalin immediate release formulations to pregabalin prolonged release

When switching from pregabalin immediate release to pregabalin prolonged release, on the day of the switch, the patient should be instructed to take the morning dose of pregabalin immediate release as prescribed and initiate pregabalin prolonged release therapy after the evening meal.

Table 1. Conversion from pregabalin immediate release to pregabalin prolonged release

^a 247.5 mg=3 X 82.5 mg tablets taken once a day.

^b 495 mg=3 X 165 mg tablets taken once a day.

^c 660 mg=2 X 330 mg tablets taken once a day.

Discontinuation of pregabalin

In accordance with current clinical practice, if pregabalin has to be discontinued, it is recommended this should be done gradually (see sections 4.4 and 4.8).

Renal impairment

Use of pregabalin prolonged-release tablets is not recommended for patients with creatinine clearance (CL_cr) less than 30 mL/min or who are undergoing haemodialysis.

In view of dose-dependent adverse reactions and because pregabalin is eliminated primarily by renal excretion, dose adjustment is needed in patients with reduced renal function. 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 (CL_cr), as indicated in Table 2 determined using the following formula:

Pregabalin is removed effectively from plasma by haemodialysis (50% of drug in 4 hours). Patients on haemodialysis should be treated with immediate release medicinal products. The treating physician should refer to the Summary of Product Characteristics of immediate release pregabalin medicinal products for guidance and dose recommendations in case of patients on haemodialysis.

Table 2. Pregabalin Prolonged Release Dose Adjustment Based on Renal Function

^a 495 mg=3 X 165 mg tablets taken once a day

^b 660 mg=2 X 330 mg tablets taken once a day

^c 247.5 mg=3 X 82.5 mg tablets taken once a day

Hepatic impairment

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

Paediatric population

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 sections 4.8, 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

Misabri PR must be taken directly after an evening meal.

Misabri PR tablet should be swallowed whole and should not be split, crushed or chewed. The tablet should not be broken because this could impact the prolonged release characteristics (see section 5.2).

Misabri PR is for oral use only.

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

Diabetic patients

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

Severe cutaneous adverse reactions (SCARs)

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).

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.

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.

Respiratory depression

There have been reports of severe respiratory depression in relation to pregabalin use. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly may be at higher risk of experiencing this severe adverse reaction. Dose adjustments may be necessary in these patients (see section 4.2).

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. Cases of suicidal ideation and behaviour have been observed in patients treated with pregabalin in the post-marketing experience (see section 4.8). An epidemiological study using a self controlled study design (comparing treatment periods with non-treatment periods within an individual) showed evidence of an increased risk of new onset 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 and appropriate 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 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).

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 concomitantly with an opioid had an increased risk for opioid-related death compared to opioid use alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19 – 2.36]). This increased risk was observed at low doses of pregabalin (≤ 300 mg, aOR 1.52 [95% CI, 1.04 – 2.22]) and there was a trend for a greater risk at high doses of pregabalin (> 300 mg, aOR 2.51 [95% CI 1.24 – 5.06]).

Misuse, abuse potential or dependence

Pregabalin can cause drug dependence, which may occur at therapeutic doses. Cases of misuse, abuse and dependence have been reported. Patients with a history of substance abuse may be at higher risk for pregabalin misuse, abuse and dependence, and pregabalin should be used with caution in such patients. Before prescribing pregabalin, the patient's risk of misuse, abuse or dependence should be carefully evaluated.

Patients treated with pregabalin should be monitored for symptoms of pregabalin misuse, abuse or dependence, such as development of tolerance, dose escalation and drug-seeking behaviour.

Withdrawal symptoms

After discontinuation of short-term and long-term treatment with pregabalin, withdrawal symptoms have been observed. The following symptoms have been reported: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, nervousness, depression, suicidal ideation, pain, convulsion, hyperhidrosis and dizziness. The occurrence of withdrawal symptoms following discontinuation of pregabalin may indicate drug dependence (see section 4.8). The patient should be informed about this at the start of the treatment. If pregabalin should be discontinued, it is recommended this should be done gradually independent of the indication (see section 4.2).

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.

Encephalopathy

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

Women of childbearing potential/Contraception

Misabri PR use in the first trimester of pregnancy may cause major birth defects in the unborn child. Pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during treatment (see section 4.6).

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 the post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking pregabalin and opioids and/or 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.

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

Women of childbearing potential have to use effective contraception during treatment (see section 4.4).

Pregnancy

Studies in animals have shown reproductive toxicity (see section 5.3).

Pregabalin has been shown to cross the placenta in rats (see section 5.2). Pregabalin may cross the human placenta.

Major congenital malformations

Data from a Nordic observational study of more than 2700 pregnancies exposed to pregabalin in the first trimester showed a higher prevalence of major congenital malformations (MCM) among the paediatric population (live or stillborn) exposed to pregabalin compared to the unexposed population (5.9% vs. 4.1%).

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)).

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 estimates imprecise.

Misabri PR 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 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).

Misabri PR may have minor or moderate influence on the ability to drive and use machines. Misabri PR 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 3 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).

Additional reactions reported from post-marketing experience are included in italics in the list below.

Table 3. Pregabalin Adverse Drug Reactions

* Alanine aminotransferase increased (ALT) and aspartate aminotransferase increased (AST).

After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms have been observed. The following symptoms have been reported: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, suicidal ideation, pain, hyperhidrosis and dizziness. These symptoms may indicate drug 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 (see sections 4.2 and 4.4).

Paediatric population

The pregabalin safety profile observed in five 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 two 1 year open label follow on safety studies, n=54 and n=431) 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 and 5.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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. 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 (see section 4.2 Table 2).

Pharmacotherapeutic group: Analgesics, other analgesics and antipyretics, gabapentinoids, ATC code: N02BF02

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 (α ₂-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.

The efficacy and safety of pregabalin prolonged release has been demonstrated in a randomised, double-blind, double-dummy, multiple-dose, multicentre, three-arm, parallel study where pregabalin prolonged release tablet (test product) was compared to placebo and reference medicinal product immediate release pregabalin hard capsule in 453 adult patients with Diabetic Peripheral Neuropathy. This was a 13-week treatment duration trial where patients were dosed with 165 mg initial dose and further up titrated to maximum 660 mg dose. The primary efficacy endpoint was Change in mean weekly pain score from baseline to end of treatment. Mean ± SD of change in mean weekly pain score from baseline to end of treatment for test, reference and placebo group were -3.43, -3.49 and -3.04 respectively. Reduction observed in mean weekly pain score was comparable between pregabalin prolonged release tablets and reference medicinal product group. A statistically significant difference was observed for both test and reference product over placebo.

The secondary endpoint of the percentage of patients with 30% reduction in weekly mean pain score in phase-III trial was 87.07%, 87.70% and 76.86% respectively for pregabalin prolonged release tablet, reference medicinal product and placebo. This difference was found to be statistically significant for both test and reference product over placebo.

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.

Pregabalin prolonged release has linear pharmacokinetics with dose-proportional increases in maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) from 82.5– 660 mg/day. Following repeated administration, steady state is achieved within approximately 72-96 hours.

Pregabalin prolonged-release administered once daily following an evening meal has equivalent AUC and lower C_max relative to a comparative dose of pregabalin (Table 4). Variability in C_max and AUC for pregabalin prolonged release is less than or equal to 25%.

Table 4 Steady-State Pharmacokinetics for pregabalin prolonged release 330 mg Once Daily and pregabalin 150 mg Twice Daily

Note: Geometric mean (%CV) for AUC_tau,ss, C_max,ss, median (range) for T_max,ss

AUC_tau,ss = area under the curve during a dosage interval at steady state at; BID = every 12 hours; C_max,ss = peak concentrations at steady state; N = Number of subjects; T_max,ss = time to peak concentrations.

Absorption

Pregabalin is absorbed from the small intestine and proximal colon. Pregabalin prolonged release absorption is linear and dose proportional.

The bioavailability of pregabalin prolonged release is reduced if taken on an empty stomach. The AUC is approximately 30-50% lower when pregabalin prolonged release is administered fasted relative to following an evening meal.

When pregabalin prolonged release is administered following a 800-1000 calorie (50% fat, 20% protein, 30% carbohydrate) evening meal, median peak plasma concentrations occur at 8 hours.

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 in subjects with normal renal function. 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 2).

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 2).

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 C_max 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 and 4.8).

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 2).

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 haemangiosarcoma was observed at higher exposures. The non-genotoxic 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.

Tablet core:

Hypromellose

Hydroxypropyl cellulose (E 463)

Basic butylated methacrylate copolymer (E 1205)

Crospovidone (Type A)

Magnesium stearate (E 470b)

Silica, colloidal anhydrous (E 551)

Tablet coating:

Polyvinyl Alcohol (E 1203)

Titanium Dioxide (E 171)

Macrogol (E 1521)

Talc (E 553b)

Iron oxide red (E 172)

Iron oxide black (E 172)

Printing ink

Shellac glaze

Iron oxide black (E 172)

Propylene glycol (E 1520)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Carton box containing white, wide-mouthed, round HDPE container with child-resistant white cap with liner and one desiccant cylinder.

Pack sizes: Original pack with 30 prolonged-release tablets, multipack with 90 (3x30) prolonged release tablets.

The desiccant should not be swallowed.

Not all pack sizes may be marketed.

No special requirements for disposal.