PREGABALIN REGULIS 75 MG HARD CAPSULES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Pregabalin Regulis 75 mg Hard Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 75 mg of pregabalin.

Excipient with known effect

Each hard capsule contains 8.25 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Hard capsule.

White and orange capsule, size 4 (approximately 14 mm).

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Neuropathic pain

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

Epilepsy

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

Generalised Anxiety Disorder

Pregabalin Regulis 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

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:

CLcr(ml/min) = [" 2.^^       \ (x 0.85 for female Patients)

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__________­___

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, 5.1 and 5.2 but no recommendation on a posology can be made.

Elderly

Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see section 5.2).

Method of administration

Pregabalin Regulis may be taken with or without food.

Pregabalin Regulis 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 post-marketing experience of hypersensitivity reactions, including cases of angioedema. Pregabalin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.

Dizziness, somnolence, loss of consciousness, confusion, and mental impairment

Pregabalin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have also been post-marketing reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medicinal product.

Vision-related effects

In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than did patients treated with placebo which resolved in a majority of cases with continued dosing. In the clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction and visual field changes was greater in pregabalin-treated patients than in placebo-treated patients; the incidence of fundoscopic changes was greater in placebo-treated patients (see section 5.1).

In the post-marketing experience, visual adverse reactions have also been reported, including loss of vision, visual blurring or other changes of visual acuity, many of which were transient. Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.

Renal failure

Cases of renal failure have been reported and in some cases discontinuation of pregabalin did show reversibility of this adverse reaction.

Withdrawal of concomitant anti-epileptic 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. 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 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). 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

Cases of misuse, abuse and dependence have been reported. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of pregabalin misuse, abuse or dependence (development of tolerance, dose escalation, drug-seeking behaviour have been reported).

Encephalopathy

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

Lactose intolerance

Pregabalin Regulis contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicinal product.

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 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.

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

Risk related to epilepsy and antiepileptic medicinal products in general The risk of birth defects is increased by a factor of 2 – 3 in the offspring of mothers treated with an antiepileptic medicinal product. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practised whenever possible. Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential and the need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child.

Risk related to pregabalin

There is a limited amount of data from the use of pregabalin in pregnant women. A population-based cohort study of 2,712 pregabalin exposed pregnancies indicates a slightly increased risk of major congenital malformations associated with the use of pregabalin in pregnancy. However, this study was subject to some limitations and further data are needed to reach a definitive conclusion.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Pregabalin Regulis 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).

4.7 Effects on ability to drive and use machines

Pregabalin Regulis may have minor or moderate influence on the ability to drive and use machines. Pregabalin Regulis 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 8,900 patients exposed to pregabalin, of whom over 5,600 were in double-blind placebo-controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 12 % for patients receiving pregabalin and 5 % for patients receiving placebo. The most common adverse reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence.

In table 2 below all adverse reactions, which occurred at an incidence greater than placebo and in more than one patient, are listed by class and frequency (very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The adverse reactions listed may also be associated with the underlying disease and/or concomitant medicinal products.

In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, CNS adverse reactions and especially somnolence was increased (see section 4.4).

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

Table 2. 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 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 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 y, 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, 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

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 Cmax by approximately 25–30 % and a delay in tmax to approximately 2.5 hours.

However, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin absorption.

Distribution

In preclinical studies, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the apparent volume of distribution of pregabalin following oral administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins. Biotransformation

Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin, approximately 98 % of the radioactivity recovered in the urine was unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9 % of the dose. In preclinical studies, there was no indication of racemisation of pregabalin S-enantiomer to the R-enantiomer.

Elimination

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance (see section 5.2 Renal impairment). Dose adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see section 4.2 Table 1).

Linearity/non-linearity

Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (< 20 %). Multiple dose pharmacokinetics are predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.

Gender

Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of pregabalin.

Renal impairment

Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by haemodialysis (following a 4 hour haemodialysis treatment plasma pregabalin concentrations are reduced by approximately 50 %). Because renal elimination is the major elimination pathway, dose reduction in patients with renal impairment and dose supplementation following haemodialysis is necessary (see section 4.2 Table 1).

Hepatic impairment

No specific pharmacokinetic studies were carried out in patients with impaired liver function. Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.

Paediatric population

Pregabalin pharmacokinetics were evaluated in paediatric patients with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years and 12 to 16 years) at dose levels of 2.5, 5, 10 and 15 mg/kg/day in a pharmacokinetic and tolerability study.

After oral administration of pregabalin in paediatric patients in the fasted state, in general, time to reach peak plasma concentration was similar across the entire age group and occurred 0.5 hours to 2 hours postdose.

Pregabalin Cmax and AUC parameters increased in a linear manner with increasing dose within each age group. The AUC was lower by 30 % in paediatric patients below a weight of 30 kg due to an increased body weight adjusted clearance of 43 % for these patients in comparison to patients weighing > 30 kg.

Pregabalin terminal half-life averaged about 3 to 4 hours in paediatric patients up to 6 years of age, and 4 to 6 hours in those 7 years of age and older. Population pharmacokinetic analysis showed that creatinine clearance was a significant covariate of pregabalin oral clearance, body weight was a significant covariate of pregabalin apparent oral volume of distribution, and these relationships were similar in paediatric and adult patients.

Pregabalin pharmacokinetics in patients younger than 3 months old have not been studied (see sections 4.2, 4.8 and 5.1).

Elderly

Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decreases in creatinine clearance associated with increasing age. Reduction of pregabalin dose may be required in patients who have age related compromised renal function (see section 4.2 Table 1).

Breast-feeding mothers

The pharmacokinetics of 150 mg pregabalin given every 12 hours (300 mg daily dose) was evaluated in 10 lactating women who were at least 12 weeks postpartum. Lactation had little to no influence on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk with average steady-state concentrations approximately 76 % of those in maternal plasma. The estimated infant dose from breast milk (assuming mean milk consumption of 150 ml/kg/day) of women receiving 300 mg/day or the maximum dose of 600 mg/day would be 0.31 or 0.62 mg/kg/day, respectively. These estimated doses are approximately 7 % of the total daily maternal dose on a mg/kg basis.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsules content

Lactose Monohydrate

Maize Starch, pregelatinised

Talc

Capsules shell

Body: Gelatin and Titanium dioxide (E171)

Cap: Gelatin and Titanium dioxide (E171), Red Iron Oxide (E172) Printing Ink: Shellac, Iron oxide black (E172), Propylene glycol

6.2 Incompatibilities

Not Applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

Aluminium/PVC blisters containing 14, 56, 70, 100, 112 and 200 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Regulis Consulting Ltd,

First Floor

St Peter's House

Market Place

Tring

HP23 5AE

8 MARKETING AUTHORISATION NUMBER(S)

PL 20646/0010

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

06/01/2022