Brieka 200 mg hard capsules

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Pregabalin
Available from:
Accord Healthcare Ireland Ltd.
ATC code:
N03A
INN (International Name):
Pregabalin
Dosage:
200 milligram(s)
Pharmaceutical form:
Capsule, hard
Therapeutic area:
ANTIEPILEPTICS
Authorization status:
Not marketed
Authorization number:
PA2315/217/006
Authorization date:
2015-08-07

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Brieka 200 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 200 mg of pregabalin

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, hard.

The 200 mg capsule is light orange, size 1 (19.5 mm), marked “PGB 200” on the body with black ink.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Neuropathic pain

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

Epilepsy

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

Generalised Anxiety Disorder

Brieka 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.

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

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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), 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 immed iately following every 4 hour haemodialysis treatment (see Table 1).

Table 1. Pregabalin dose adjustment based on renal function

Creatinine

clearance (CL c r ) (ml/min)

Total pregabalin daily dose *

Dose regimen

Starting dose

(mg/day)

Maximum dose

(mg/day)

≥ 60

B I D or TID

≥30 - <60

B I D or TID

≥15 - <30

25 – 50**

Once Daily or BID

< 15

25**

Once Daily

Supplementary dosage following haemodialysis (mg)

25**

Single dose+

T I D = Three divided doses

B I D = 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 Brieka 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).

Method of administration

Brieka may be taken with or without food.

Brieka 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.

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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 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 post‑marketing reports of congestive heart failure in some patients receiving pregabalin. These reactions are

mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication.

Pregabalin should be used with caution in these patients. Discontinuation of pregabalin may resolve the reaction.

Treatment of central neuropathic pain due to spinal cord injury

In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, central

nervous system adverse reactions and especially somnolence was increased. This may be attributed to an additive effect due to

concomitant medicinal products (e.g. anti‑spasticity agents) needed for this condition. This should be considered when

prescribing pregabalin in this condition.

Suicidal ideation and 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.

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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 interactions

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 invitro, 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 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.

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Brieka 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 in 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).

4.7 Effects on ability to drive and use machines

Brieka may have minor or moderate influence on the ability to drive and use machines. Brieka 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

The pregabalin clinical programme involved over 8900 patients who were exposed to pregabalin, of whom over 5600 were in

double‑blind placebo controlled trials. The most commonly reported adverse reactions were dizziness and somnolence.

Adverse reactions were usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse

reactions was 12 % for patients receiving pregabalin and 5 % for patients receiving placebo. The most common adverse

reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence.

In 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).

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

Table 2. Pregabalin Adverse Drug Reactions

System Organ Class

Adverse drug reactions

Infections and infestations

Common

Nasopharyngitis

Blood and lymphatic system disorders

Uncommon

Neutropaenia

Immune system disorders

Uncommon

Rare

Hypersensitivity

Angioedema, allergic reaction

Metabolism and nutrition disorders

Common

Appetite increased

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System Organ Class

Adverse drug reactions

Uncommon

Anorexia, hypoglycaemia

Psychiatric disorders

Common

Uncommon

Rare

Euphoric mood, confusion, irritability, disorientation, insomnia, libido

decreased

Hallucination, panic attack, restlessness, agitation, depression,

depressed mood, elevated mood, aggression, mood swings,

depersonalisation, word finding difficulty, abnormal dreams, libido

increased, anorgasmia, apathy

Disinhibition

Nervous system disorders

Very Common

Common

Uncommon

Rare

Dizziness, somnolence, headache

Ataxia, coordination abnormal, tremor, dysarthria, amnesia, memory

impairment, disturbance in 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

Convulsions, parosmia, hypokinesia, dysgraphia

Eye disorders

Common

Uncommon

Rare

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

Vision loss, keratitis,oscillopsia, altered visual depth perception,

mydriasis, strabismus, visual brightness

Ear and labyrinth disorders

Common

Uncommon

Vertigo

Hyperacusis

Cardiac disorders

Uncommon

Rare

Tachycardia, atrioventricular block first degree, sinus bradycardia,

congestive heart failure

QT prolongation, sinus tachycardia, sinus arrhythmia

Vascular disorders

Uncommon

Hypotension, hypertension, hot flushes, flushing, peripheral coldness

Respiratory, thoracic and mediastinal disorders

Uncommon

Rare

Dyspnoea, epistaxis, cough, nasal congestion, rhinitis, snoring, nasal

dryness

Pulmonary oedema , throat tightness

Gastrointestinal disorders

Common

Uncommon

Rare

Vomiting, nausea, constipation, diarrhoea, flatulence, abdominal

distension, dry mouth

Gastrooesophageal reflux disease, salivary hypersecretion,

hypoaesthesia oral

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System Organ Class

Adverse drug reactions

Ascites, pancreatitis, swollen tongue, dysphagia

Skin and subcutaneous tissue disorders

Uncommon

Rare

Rash papular, urticaria, hyperhidrosis, pruritus

Stevens Johnson syndrome, cold sweat

Musculoskeletal and connective tissue disorders

Common

Uncommon

Rare

Muscle cramp, arthralgia, back pain, pain in limb, cervical spasm

Joint swelling, myalgia, muscle twitching, neck pain , muscle stiffness

Rhabdomyolysis

Renal and urinary disorders

Uncommon

Rare

Urinary incontinence, dysuria

Renal failure, oliguria, urinary retention

Reproductive system and breast disorders

Common

Uncommon

Rare

Erectile dysfunction

Sexual dysfunction, ejaculation delayed, dysmenorrhoea, breast pain

Amenorrhoea, breast discharge, breast enlargement, gynaecomastia

General disorders and administration site conditions

Common

Uncommon

Oedema peripheral, oedema, gait abnormal, fall, feeling drunk,

feeling abnormal, fatigue

Generalised oedema,face oedema, chest tightness, pain, pyrexia,

thirst, chills, asthenia

Investigations

Common

Uncommon

Rare

Weight increased

Blood creatine phosphokinase increased, alanine aminotransferase

increased, aspartate aminotransferase increased, blood glucose

increased, platelet count decreased, blood creatinine increased,

blood potassium decreased, weight decreased

White blood cell count 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 three paediatric studies in patients with partial seizures with or without secondary

generalization (12‑week efficacy and safety study in patients with partial onset seizures, n=295;

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 (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

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adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

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 1).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, other antiepileptics, 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 (α

-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

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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 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 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.

Monotherapy (newly diagnosed patients)

Pregabalin has been studied in 1 controlled clinical trial of 56 week duration with BID. 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, patients with epilepsy receiving anti‑epileptic

drugs and patients with chronic pain.

Absorption

Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within 1 hour

following both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥ 90 % and is

independent of dose. Following repeated administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin

absorption is decreased when given with food resulting in a decrease in C

by approximately 25‑30 % and a delay in t

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

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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 C

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.

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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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsules content

Mannitol

Co-processed starch (pregelatinised starch and maize starch)

Talc

Capsules shell

Gelatin

Titanium dioxide (E171)

Red Iron Oxide (E172)

Printing Ink

Shellac

Black Iron Oxide (E172)

Potassium hydroxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

Health Products Regulatory Authority

20 January 2020

CRN009DY6

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6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Aluminium/PVC blisters containing 14, 21, 30, 56, 60, 84, 90 or 100 capsules, hard.

HDPE bottle with LDPE lid or PP screw cap containing 100 capsules, hard.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Accord Healthcare Ireland Ltd.

Euro House

Euro Business Park

Little Island

Cork T45 K857

Ireland

8 MARKETING AUTHORISATION NUMBER

PA2315/217/006

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 7

August 2015

Date of last renewal: 11

June 2020

10 DATE OF REVISION OF THE TEXT

January 2020

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