Rewisca 25 Mg Hard Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Rewisca 25 mg hard capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 25 mg pregabalin.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Hard capsule
The body of the capsule is white colour, the cap of the capsule is white colour. Capsule cap is imprinted with black mark P25. The content of the capsule is white to off white powder.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Epilepsy
Rewisca is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.
Generalised Anxiety Disorder
Rewisca is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.
4.2 Posology and method of administration
Posology
The dose range is 150 to 600 mg per day given in either two or three divided doses.
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).
Patients 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 individualised 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
|
Creatinine clearance (CLcr) (ml/min) |
Total pregabalin daily dose * |
Dose regimen | |
|
Starting dose (mg/day) |
Maximum dose (mg/day) | ||
|
> 60 |
150 |
600 |
BID or TID |
|
>30 - <60 |
75 |
300 |
BID or TID |
|
>15 - <30 |
25 - 50 |
150 |
Once daily or |
|
<15 |
25 |
75 |
Once daily |
|
Supplementary dosage following haemodialysis (mg) | |||
|
25 |
100 |
Single dose+ | |
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 Patients with 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 section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.
Elderly (over 65 years of age) _ population
Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see patients with renal impairment).
Method of administration
Rewisca may be taken with or without food.
Rewisca is for oral use only.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
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 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, 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.
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. Pregabalin should be used with caution in these patients. Discontinuation of pregabalin may resolve the reaction.
Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic 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 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).
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.
4.5 Interaction with other medicinal products and other forms of interaction
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.
Interactions and the elderly
No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
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
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.
Rewisca 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 theraphy 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).
4.7 Effects on ability to drive and use machines
Rewisca may have minor or moderate influence on the ability to drive and use machines.
Rewisca 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.
4.8 Undesirable effects
Summary of the safety profile
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.
Tabulated list of adverse reactions
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.
Additional reactions reported from post-marketing experience are included in italics in the list below.
Table 2. Pregabalin Adverse Drug Reactions
Infections and infestations
Common Nasopharyngitis
Blood and lymphatic system disorders
Uncommon Neutropaenia
Immune system disorders
Uncommon Hypersensitivity
Rare Angioedema, allergic reaction
Metabolism and nutrition disorders
Common Appetite increased
|
Uncommon |
Anorexia, hypoglycaemia |
|
Psychiatric disorders Common |
Euphoric mood, confusion, irritability, disorientation, insomnia, libido decreased |
|
Uncommon |
Hallucination, panic attack, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood swings, depersonalisation, word finding difficulty, abnormal dreams, libido increased, anorgasmia, apathy |
|
Rare |
Disinhibition |
Nervous system disorders
Very common Dizziness, somnolence, headache
|
Common |
Ataxia, coordination abnormal, tremor, dysarthria, amnesia, memory impairment, disturbance in |
|
Uncommon |
attention, paraesthesia, hypoaesthesia, sedation, balance disorder, lethargy Syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, dizziness postural, intention tremor, nystagmus, cognitive disorder, mental impairment, speech disorder, hyporeflexia, hyperaesthesia, burning sensation, ageusia, malaise |
|
Rare |
Convulsions, parosmia, hypokinesia, dysgraphia |
|
Eye disorders Common Uncommon |
Vision blurred, diplopia Peripheral vision loss, visual disturbance, eye swelling, visual field defect, visual acuity reduced, eye pain, asthenopia, photopsia, dry eye, lacrimation increased, eye irritation |
|
Rare |
Vision loss, keratitis, oscillopsia, altered visual depth perception, mydriasis, strabismus, visual brightness |
Ear and labyrinth disorders
Common Vertigo
Uncommon Hyperacusis
Cardiac disorders
Uncommon
Tachycardia, atrioventricular block first degree, sinus
bradycardia, congestive heart failure
Rare QT prolongation, sinus tachycardia, sinus arrhythmia
Vascular disorders
Uncommon Hypotension, hypertension, hot flushes, flushing,
peripheral coldness
Respiratory, thoracic and mediastinal disorders
Uncommon Dyspnoea, epistaxis, cough, nasal congestion,
rhinitis, snoring, nasal dryness Rare Pulmonary oedema, throat tightness
Gastrointestinal disorders
Common Vomiting, nausea, constipation, diarrhoea,
flatulence, abdominal distension, dry mouth Uncommon Gastrooesophageal reflux disease, salivary
hypersecretion, hypoaesthesia oral
Rare Ascites, pancreatitis, swollen tongue, dysphagia
Skin and subcutaneous tissue disorders
Uncommon Rash papular, urticaria, hyperhidrosis, pruritus
Rare Stevens Johnson syndrome, cold sweat
Musculoskeletal and connective tissue disorders
Common Muscle cramp, arthralgia, back pain, pain in limb,
cervical spasm
Uncommon Joint swelling, myalgia, muscle twitching, neck pain,
muscle stiffness
Rare Rhabdomyolysis
Renal and urinary disorders
Uncommon Urinary incontinence, dysuria
Rare Renal failure, oliguria, urinary retention
Reproductive system and breast disorders
Common Erectile dysfunction
Uncommon Sexual dysfunction, ejaculation delayed,
dysmenorrhoea, breast pain
Rare Amenorrhoea, breast discharge, breast enlargement,
gynaecomastia
General disorders and administration site conditions
Common Oedema peripheral, oedema, gait abnormal, fall,
feeling drunk, feeling abnormal, fatigue Uncommon Generalised oedema, face oedema, chest tightness,
pain, pyrexia, thirst, chills, asthenia
Investigations
Common Weight increased
Uncommon Blood creatine phosphokinase increased, alanine
aminotransferase increased, aspartate aminotransferase increased, blood glucose increased, platelet count decreased, blood creatinine increased, blood potassium decreased, weight decreased
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 two paediatric studies (pharmacokinetic and tolerability study, n=65; 1 year open label follow on safety study, n=54) was similar to that observed in the adult studies (see sections 4.2,
5.1 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.
4.9 Overdose
Symptoms
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. In rare occasions, cases of coma have been reported.
Management
Treatment of pregabalin overdose should include general supportive measures and may include haemodialysis if necessary (see section 4.2 Table 1).
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-epileptics, other anti-epileptics; ATC code: N03AX16.
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 (a2-5 protein) of voltage-gated calcium channels in the central nervous system.
Clinical efficacy and safety
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) were similar to those observed in adults. Results of 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 (see sections 4.2, 4.8 and 5.2).
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. Ophthamologic 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.
5.2 Pharmacokinetic properties
Pregabalin steady-state pharmacokinetics are similar in healthy volunteers and patients with epilepsy receiving anti-epileptic drugs.
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 (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 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.
5.3 Preclinical safety data
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.
6.1 List of excipients
Capsule contents:
Pregelatinised starch Talc (E553b)
Capsule shell:
Titanium dioxide (E171)
Gelatin (E441)
Black printing ink (shellac (E904), black iron oxide (E172), N-butyl alcohol, purified water, propylene glycol (E1520), dehydrated ethanol, isopropyl alcohol, ammonium hydroxide (E527))
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
Blister (PVC/PVDC//Al): 14, 21, 56, 70, 84, 100 or 112 (2 x 56) hard capsules, in a box.
Not all pack sizes may be marketed.
Special precautions for disposal
6.6
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Consilient Health Limited, 5th Floor, Beaux Lane House, Mercer Street Lower, Dublin 2, Ireland
8 MARKETING AUTHORISATION NUMBER(S)
PL 24837/0061
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
23/12/2014
10 DATE OF REVISION OF THE TEXT
09/02/2016