Linefor

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINEFOR

Composition:

Active substance: pregabalin;

1 capsule contains pregabalin 75 mg, or 150 mg, or 300 mg;

Excipients: lactose monohydrate; maize starch; talc;

Capsule shell for 75 mg and 300 mg capsules: gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172);

Capsule shell for 150 mg capsules: gelatin, titanium dioxide (E 171);

Printing ink: shellac, black iron oxide (E 172), propylene glycol, ammonium hydroxide.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

75 mg capsules – hard gelatin capsules with a white body and reddish-brown cap, marked "75" on the body; capsule size № 3;

150 mg capsules – hard gelatin capsules white in colour, marked "150" on the body; capsule size № 1;

300 mg capsules – hard gelatin capsules with a white body and reddish-brown cap, marked "300" on the body; capsule size № 0.

Pharmacotherapeutic group. Analgesics. Other analgesics and antipyretics. Gabapentinoids. Pregabalin.

ATC code N02BF02.

Pharmacological Properties

Pharmacodynamics

The active substance, pregabalin, is a gamma-aminobutyric acid analogue [(S)-3-(aminomethyl)hexanoic acid].

Mechanism of Action

Pregabalin binds to the auxiliary subunit (α2-δ protein) of voltage-dependent calcium channels in the central nervous system (CNS).

Clinical Efficacy and Safety

• Neuropathic Pain

The efficacy of pregabalin has been demonstrated in clinical studies for the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of the drug has not been studied in other types of neuropathic pain.

Pregabalin was studied in 10 controlled clinical trials lasting up to 13 weeks with a dosing regimen of twice daily, and in trials lasting up to 8 weeks with a regimen of three times daily. Overall, the safety and efficacy profiles for the twice-daily and three-times-daily regimens were similar.

In clinical trials lasting up to 12 weeks, in which the drug was used for the treatment of neuropathic pain, reduction in peripheral and central pain was observed after the first week and persisted throughout the treatment period.

In controlled clinical trials studying peripheral neuropathic pain, a 50% improvement on the pain rating scale was observed in 35% of patients receiving pregabalin and in 18% of patients receiving placebo. Among patients who did not experience somnolence, such improvement was observed in 33% of patients receiving pregabalin and in 18% of patients in the placebo group. Among patients who experienced somnolence, the proportion of responders was 48% in the pregabalin group and 16% in the placebo group.

In a controlled clinical trial studying centrally mediated neuropathic pain, a 50% improvement on the pain rating scale was observed in 22% of patients receiving pregabalin and in 7% of patients receiving placebo.

• Epilepsy

Adjunctive Therapy. Pregabalin was studied in three controlled clinical trials lasting 12 weeks with dosing regimens of twice or three times daily. Overall, the safety and efficacy profiles for the twice-daily and three-times-daily regimens were similar.

Reduction in seizure frequency was observed as early as the first week.

Children. The efficacy and safety of pregabalin as adjunctive therapy for epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study involving patients aged 3 months to 16 years (n=65) with partial seizures were similar to those in adults. Results from a 12-week placebo-controlled study involving 295 children aged 4 to 16 years, a 14-day study involving 175 children aged 1 month to 4 years, both evaluating the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and two open-label safety studies lasting 1 year involving 54 and 431 children aged 3 months to 16 years with epilepsy, indicate that adverse reactions such as pyrexia and upper respiratory tract infections occur more frequently in children than in adult patients with epilepsy (see sections "Pharmacokinetics", "Dosage and Administration", and "Adverse Reactions").

In the 12-week placebo-controlled study, children received pregabalin at 2.5 mg/kg/day (maximum 150 mg/day), pregabalin at 10 mg/kg/day (maximum 600 mg/day), or placebo. A reduction of at least 50% in partial seizures from baseline was observed in 40.6% of patients receiving pregabalin at 10 mg/kg/day (p=0.0068 vs placebo), in 29.1% of patients receiving pregabalin at 2.5 mg/kg/day (p=0.2600 vs placebo), and in 22.6% of those receiving placebo.

In the 14-day placebo-controlled study, children (aged 1 month to 4 years) received pregabalin at 7 mg/kg/day, pregabalin at 14 mg/kg/day, or placebo. The median seizure frequency at baseline and at the end of the study was 4.7 and 3.8, respectively, for pregabalin at 7 mg/kg/day; 5.4 and 1.4, respectively, for pregabalin at 14 mg/kg/day; and 2.9 and 2.3 for placebo. Pregabalin at 14 mg/kg/day significantly reduced the logarithmically transformed frequency of partial seizures compared to placebo (p=0.0223); pregabalin at 7 mg/kg/day did not show improvement compared to placebo.

In a 12-week placebo-controlled study of patients with primary generalized tonic-clonic (PGTC) seizures, 219 patients aged 5 to 65 years (including 66 aged 5 to 16 years) received pregabalin at 5 mg/kg/day (maximum 300 mg/day), 10 mg/kg/day (maximum 600 mg/day), or placebo as adjunctive therapy. At least a 50% reduction in PGTC seizure frequency was observed in 41.3%, 38.9%, and 41.7% of patients receiving pregabalin at 5 mg/kg/day, pregabalin at 10 mg/kg/day, and placebo, respectively.

Monotherapy (in patients with newly diagnosed disease). Pregabalin was studied in one controlled clinical trial lasting 56 weeks with a twice-daily dosing regimen. Pregabalin demonstrated non-inferior efficacy compared to lamotrigine, based on the 6-month endpoint assessment of seizure-free status. Pregabalin and lamotrigine were equally safe and well tolerated.

• Generalized Anxiety Disorder

Pregabalin was studied in six controlled trials lasting 4–6 weeks, one 8-week trial involving elderly patients, and one long-term relapse prevention trial with a double-blind relapse prevention phase lasting 6 months.

Reduction in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Rating Scale (HAM-A) was observed as early as week 1.

In controlled clinical trials (lasting 4–8 weeks), a ≥50% improvement in total HAM-A score from baseline to endpoint was observed in 52% of patients receiving pregabalin and in 38% of patients in the placebo group.

During controlled trials, blurred vision occurred more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this effect resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundus examination with dilated pupils) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity worsened in 6.5% of patients in the pregabalin group and in 4.8% in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and in 11.7% of patients in the placebo group. Fundus changes were observed in 1.7% of patients receiving pregabalin and in 2.1% of patients in the placebo group.

• Fibromyalgia

The efficacy of pregabalin was established in one 14-week double-blind, placebo-controlled, multicenter trial (F1) and one 6-week randomized withdrawal trial (F2). Patients with a diagnosis of fibromyalgia based on American College of Rheumatology criteria (widespread pain for at least 3 months and pain in 11 or more of 18 specific tender points) were enrolled. The trials demonstrated reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global impression and fibromyalgia impact questionnaire.

Children. A 15-week placebo-controlled trial was conducted in 107 adolescents aged 12–17 years with fibromyalgia, who received pregabalin at doses of 75–450 mg/day. The primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured on an 11-point rating scale) showed numerically greater improvement in patients receiving pregabalin compared to those receiving placebo, but this improvement did not reach statistical significance. The most commonly observed adverse reactions in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics

The pharmacokinetic parameters of pregabalin are similar in healthy volunteers, patients with epilepsy taking antiepileptic drugs, and patients with chronic pain.

Absorption. Pregabalin is rapidly absorbed after oral administration on an empty stomach and reaches maximum plasma concentration (Cmax) within 1 hour after single and multiple doses. The estimated oral bioavailability of pregabalin is 90% or more and is dose-independent. Steady-state concentrations are achieved within 24–48 hours after repeated administration. The extent of pregabalin absorption is reduced when taken with food, resulting in approximately a 25–30% decrease in Cmax and a delay in time to reach maximum concentration (tmax) by about 2.5 hours. However, administration of pregabalin with food did not have a clinically significant effect on the overall extent of absorption.

Distribution. Pregabalin readily crosses the blood-brain barrier in animals, as well as the placenta in animals and into milk during lactation. In humans, the apparent volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin does not bind to plasma proteins.

Metabolism. In humans, pregabalin undergoes minimal metabolism. After administration of a radiolabeled dose of pregabalin, approximately 98% of radioactivity is excreted in urine as unchanged pregabalin. The N-methylated derivative of pregabalin (the main metabolite detected in urine) accounted for 0.9% of the administered dose.

Elimination. Pregabalin is eliminated from systemic circulation primarily by renal excretion in unchanged form. The mean elimination half-life of pregabalin is 6.3 hours. Plasma and renal clearance of pregabalin are directly proportional to creatinine clearance. Dose adjustment is required for patients with renal impairment or those undergoing hemodialysis.

Linearity / Non-linearity. The pharmacokinetics of pregabalin are linear over the entire recommended dose range. Inter-subject pharmacokinetic variability for pregabalin is low (less than 20%). Pharmacokinetics of multiple doses are predictable based on single-dose data. Therefore, routine monitoring of plasma concentrations of pregabalin is not necessary.

Pharmacokinetics in Specific Patient Populations

Gender. There is no clinically significant effect of gender on plasma concentrations of pregabalin.

Renal Impairment. Pregabalin clearance is directly proportional to creatinine clearance. Additionally, pregabalin is effectively removed from plasma during hemodialysis (after 4 hours of hemodialysis, plasma concentration of pregabalin decreases by approximately 50%). Since renal excretion is the main elimination pathway, dose reduction is required for patients with renal impairment, and an additional dose should be administered after hemodialysis.

Hepatic Impairment. No specific pharmacokinetic studies have been conducted in patients with hepatic impairment. Since pregabalin undergoes negligible metabolism and is primarily excreted unchanged in urine, it is unlikely that hepatic impairment would affect plasma concentrations of pregabalin.

Children. The pharmacokinetics of pregabalin were evaluated in children with epilepsy (age groups: 1–23 months, 2–6 years, 7–11 years, and 12–16 years) receiving doses of 2.5, 5, 10, and 15 mg/kg/day in a pharmacokinetic and tolerability study. After oral administration of pregabalin to children on an empty stomach, the time to reach maximum plasma concentration was generally similar across all age groups, ranging from 0.5 to 2 hours after dosing. Cmax and area under the concentration-time curve (AUC) values increased linearly with increasing dose in each age group. In children with body weight below 30 kg, AUC values were 30% lower due to a 43% increase in body weight-adjusted clearance in these patients compared to patients with body weight ≥30 kg.

The elimination half-life of pregabalin averaged approximately 3–4 hours in children under 6 years of age and 4–6 hours in children aged 7 years and older.

Population pharmacokinetic analysis showed that creatinine clearance was a significant covariate for oral pregabalin clearance, and body weight was a significant covariate for the apparent volume of distribution of oral pregabalin, and this relationship was similar in children and adult patients.

The pharmacokinetics of pregabalin have not been studied in patients under 3 months of age (see sections "Pharmacodynamics", "Dosage and Administration", and "Adverse Reactions").

Elderly Patients. Pregabalin clearance tends to decrease with age. This decrease in oral pregabalin clearance is consistent with the age-related decline in creatinine clearance. Dose reduction of pregabalin may be required in patients with age-related renal impairment (see section "Dosage and Administration", table).

Lactation Period. The pharmacokinetics of pregabalin were evaluated in 10 breastfeeding women who received pregabalin at a dose of 150 mg every 12 hours (daily dose 300 mg), at least 12 weeks postpartum. Breastfeeding had no effect or only a negligible effect on the pharmacokinetics of pregabalin. Pregabalin was excreted into breast milk, with average steady-state concentrations approximately 76% of maternal plasma concentrations. The calculated infant dose from breast milk (assuming average milk intake of 150 mL/kg/day) from a woman taking pregabalin at 300 mg/day or at the maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the total daily maternal dose normalized to mg/kg.

Clinical Characteristics

Indications

Neuropathic Pain

Treatment of peripheral or central neuropathic pain in adults.

Epilepsy

Adjunctive therapy for partial seizures with or without secondary generalization in adults.

Generalized Anxiety Disorder

Treatment of generalized anxiety disorder in adults.

Fibromyalgia.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction

Since pregabalin is predominantly excreted unchanged in the urine, undergoes minimal metabolism in the human body (less than 2% of the dose is excreted in urine as metabolites), does not inhibit in vitro metabolism of other drugs, and does not bind to plasma proteins, it is unlikely that pregabalin would cause or be subject to pharmacokinetic interactions.

In vivo studies and population pharmacokinetic analysis

Accordingly, in in vivo studies, no clinically significant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol. Population pharmacokinetic analysis showed that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate had no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and/or ethinylestradiol

Concomitant administration of pregabalin and oral contraceptives, norethisterone and/or ethinylestradiol does not affect the steady-state pharmacokinetics of either agent.

Medicinal products affecting the CNS

Pregabalin may potentiate the effects of ethanol and lorazepam. In the post-marketing period, cases of respiratory depression, coma, and fatal outcomes have been reported in patients who concurrently received pregabalin with opioids and/or other CNS depressants. Pregabalin enhanced cognitive and gross motor function impairment caused by oxycodone.

Interactions in elderly patients

No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Drug interaction studies have been performed only in adult patients.

Special precautions for use

Patients with diabetes mellitus

According to current clinical practice, some diabetic patients who experience weight gain during pregabalin treatment may require adjustment of their antihyperglycaemic medication dosage.

Hypersensitivity reactions

Post-marketing reports have described hypersensitivity reactions, including cases of angioedema. If symptoms of angioedema such as swelling of the face, perioral area, or upper airways occur, pregabalin should be discontinued immediately.

Severe skin adverse reactions (SSARs)

Rare cases of severe skin adverse reactions (SSARs), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported during pregabalin treatment. These reactions may be life-threatening or fatal. Patients should be informed of the signs and symptoms, and skin reactions should be closely monitored. If signs or symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative therapy considered (if necessary).

Dizziness, somnolence, loss of consciousness, confusion, and psychiatric disturbances

Pregabalin use has been associated with dizziness and somnolence, which may increase the frequency of accidental injuries (falls) in elderly patients. During the post-marketing period, cases of loss of consciousness, confusion, and cognitive impairment have been reported. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of the drug.

Visual disorders

In controlled studies, a higher proportion of patients receiving pregabalin reported blurred vision compared to those receiving placebo. These effects mostly resolved with continued treatment. In clinical trials involving ophthalmological examinations, the incidence of decreased visual acuity and visual field changes was higher in patients taking pregabalin than in those receiving placebo; however, the incidence of fundus changes was higher in the placebo group (see section "Pharmacodynamics").

In the post-marketing period, adverse effects related to the eye have also been reported, including vision loss, blurred vision, or other changes in visual acuity, most of which were transient. These ocular symptoms may resolve or diminish after discontinuation of pregabalin.

Renal impairment

Cases of renal impairment have been reported. This effect was sometimes reversible after discontinuation of pregabalin.

Discontinuation of concomitant antiepileptic drugs

There is insufficient data on the discontinuation of concomitant antiepileptic drugs after seizure control has been achieved by adding pregabalin to ongoing treatment, with the aim of switching to pregabalin monotherapy.

Heart failure

During the post-marketing period, cases of congestive heart failure have been reported in some patients taking pregabalin. This reaction usually occurred during pregabalin treatment for neuropathic pain in elderly patients with pre-existing cardiovascular disorders. Pregabalin should be used with caution in such patients. This condition may resolve upon discontinuation of pregabalin.

Treatment of central neuropathic pain due to spinal cord injury

During treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly those affecting the central nervous system such as somnolence, was increased. This may be explained by an additive effect of other medications (e.g., antispastic agents) required for the treatment of this condition. This should be taken into account when prescribing pregabalin for this indication.

Respiratory depression

Cases of severe respiratory depression associated with pregabalin treatment have been reported. Patients with respiratory or neurological disorders, renal impairment, those taking other centrally acting depressant drugs, or elderly patients may be at higher risk of this serious adverse reaction. Dose adjustment may be necessary in these patient groups.

Suicidal thoughts and behaviour

Suicidal thoughts and behaviour have been observed in patients treated with antiepileptic drugs for various indications. A slightly increased risk of suicidal thoughts and behaviour exists with the use of antiepileptic medicinal products. The mechanism underlying this risk is unknown.

Cases of suicidal thoughts and behaviour have been observed in patients receiving pregabalin during the post-marketing period (see section "Adverse reactions"). An epidemiological study using a self-controlled design (comparing treatment periods with non-treatment periods within individual patients) demonstrated an increased risk of new-onset suicidal behaviour and fatal outcomes due to suicide in patients taking pregabalin.

Patients (and their caregivers) should seek medical help if suicidal thoughts or behaviour occur. Close monitoring for signs of suicidal thoughts and behaviour is necessary, and appropriate treatment should be initiated if such signs appear. Consideration should be given to discontinuing pregabalin therapy if suicidal thoughts or behaviour emerge.

Lower gastrointestinal tract disorders

Post-marketing reports have described lower gastrointestinal tract disorders (such as intestinal obstruction, paralytic ileus, constipation) associated with pregabalin use in combination with medicinal products that may cause constipation, such as opioid analgesics. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be taken (especially in women and elderly patients).

Concomitant use with opioids

Caution is recommended when prescribing pregabalin concomitantly with opioids due to the risk of central nervous system (CNS) depression (see section "Interaction with other medicinal products and other forms of interaction"). In a case-control study of opioid users, patients receiving pregabalin in combination with an opioid had an increased risk of opioid-related mortality compared to those receiving opioids alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19–2.36]). This increased risk was observed at low pregabalin doses (≤ 300 mg, aOR 1.52 [95% CI, 1.04–2.22]), and a trend toward increased risk was observed at higher pregabalin doses (> 300 mg, aOR 2.55 [95% CI, 1.24–5.06]).

Abuse, misuse, dependence

Pregabalin may cause drug dependence, which may occur even at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance abuse may be at higher risk of pregabalin misuse, abuse, and dependence, and pregabalin should therefore be used with caution in such patients. The risk of misuse, abuse, or dependence should be carefully assessed before initiating pregabalin therapy.

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

Withdrawal symptoms

Withdrawal symptoms have been observed in some patients after discontinuation of short- and long-term pregabalin treatment. Reported events include insomnia, headache, nausea, anxiety, diarrhoea, flu-like symptoms, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness, indicating physical dependence (see section "Adverse reactions"). The emergence of withdrawal symptoms after stopping pregabalin may indicate drug dependence (see section "Adverse reactions"). This information should be communicated to the patient prior to initiating treatment.

If pregabalin treatment needs to be discontinued, it is recommended to do so gradually over at least one week, regardless of the indication (see section "Dosage and administration").

Seizures, including status epilepticus and generalized seizures, may occur during pregabalin treatment or shortly after discontinuation.

Regarding discontinuation of long-term pregabalin therapy, available data suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.

Encephalopathy

Cases of encephalopathy have been reported, primarily in patients with concomitant conditions that may predispose to encephalopathy.

Women of childbearing potential / contraception

Pregabalin use during the first trimester of pregnancy may cause major congenital malformations in the fetus. Pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment (see section "Pregnancy and breastfeeding").

Excipients

The medicinal product contains propylene glycol, which may cause symptoms similar to those of alcohol intoxication.

The medicinal product contains lactose. Patients with known sugar intolerance should consult their physician before taking this medicinal product.

Capsule 75 mg contains 27 mg of lactose.

Capsule 150 mg contains 54 mg of lactose.

Capsule 300 mg contains 108 mg of lactose.

Use during pregnancy or breastfeeding

Women of childbearing potential / contraceptive methods for women

Women of childbearing potential should use effective contraception during treatment (see section "Special precautions for use").

Pregnancy

Animal studies have demonstrated reproductive toxicity. The potential risk in humans is unknown.

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

Major congenital malformations

Observational data from Scandinavian countries, involving over 2700 pregnancies, showed a higher prevalence of major congenital malformations (MCMs) in the paediatric population (live or stillborn children) exposed to pregabalin during the first trimester compared to unexposed populations (5.9% vs. 4.1%).

The risk of MCMs in children whose mothers used pregabalin during the first trimester was slightly higher compared to children not exposed in utero (adjusted prevalence ratio and 95% confidence interval: 1.14 (0.96–1.35)), and compared to children exposed to lamotrigine (1.29 (1.01–1.65)) or duloxetine (1.39 (1.07–1.82)).

Analysis of specific malformations showed a higher risk of malformations of the nervous system, eyes, orofacial clefts, urinary tract, and genital organs, although the number of such malformations was small and estimates imprecise.

Pregabalin should not be used during pregnancy except in exceptional cases where the benefit to the mother clearly outweighs the potential risk to the fetus.

Breastfeeding

A small amount of pregabalin has been detected in the breast milk of lactating women. Women who are breastfeeding should be advised not to breastfeed during pregabalin treatment.

Fertility

There are no clinical data on the effect of pregabalin on female reproductive function.

In a clinical study on the effect of pregabalin on sperm motility, healthy male volunteers received pregabalin 600 mg/day. After three months of treatment, no effect on sperm motility was observed.

In fertility studies, a negative effect on reproductive function in female rats and on reproductive function and development in male rats was demonstrated. The clinical relevance of these findings is unknown.

Ability to influence driving and use of machines

Pregabalin may have a minor or moderate influence on the ability to drive or use machines. Pregabalin may cause dizziness and somnolence and may affect the ability to drive a car or operate machinery. Therefore, patients should be advised to refrain from driving or operating complex machinery until they know how the drug affects their reaction speed.

Administration and Dosage

Route of Administration

Lenefor should be taken independently of food intake.

This medicinal product is intended for oral use only.

Doses

The dose range of the drug may vary between 150–600 mg per day. The daily dose should be divided into 2 or 3 administrations.

Neuropathic Pain

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the individual response and tolerability, the dose may be increased to 300 mg per day after 3–7 days, and if necessary, to the maximum dose of 600 mg per day after another 7 days.

Epilepsy

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the individual response and tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week, the dose may be increased to the maximum of 600 mg per day.

Generalized Anxiety Disorder

The dose, divided into 2 or 3 administrations, may range between 150–600 mg per day. The need for continued therapy should be periodically reviewed.

Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on the individual response and tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week of treatment, the dose may be increased to 450 mg per day. After an additional week, the dose may be increased to the maximum of 600 mg per day.

Fibromyalgia

The recommended dose of the drug for the treatment of fibromyalgia is 300–450 mg per day. Treatment should be initiated at a dose of 75 mg twice daily (150 mg per day). Depending on efficacy and tolerability, the dose may be increased to 150 mg twice daily (300 mg per day) within one week. For patients in whom a dose of 300 mg per day is insufficiently effective, the dose may be increased to 225 mg twice daily (450 mg per day). Although a study has been conducted using a dose of 600 mg per day, there is no evidence that this dose provides additional benefit; furthermore, this dose was associated with poorer tolerability. Considering dose-dependent adverse reactions, doses above 450 mg per day are not recommended. Since the drug is primarily eliminated via the kidneys, dosage adjustment is required in patients with renal impairment.

Discontinuation of Pregabalin

According to current clinical practice, pregabalin therapy should be discontinued gradually over at least one week, regardless of the indication (see sections "Special Warnings and Precautions" and "Adverse Reactions").

Renal Impairment

Pregabalin is eliminated from systemic circulation in unchanged form, predominantly via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage should be individually adjusted in patients with renal impairment as indicated in the table below, based on creatinine clearance (CLcr), calculated using the appropriate formula.

Pregabalin is effectively removed from plasma by hemodialysis (50% of the drug within 4 hours). For patients undergoing hemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, an extra dose of the drug should be administered immediately after each 4-hour hemodialysis session (see table).

* The total daily dose (mg/day) should be divided into several doses according to the dosing regimen to obtain the single dose (mg/dose).

• Additional dose means an extra single dose.

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment (see section "Pharmacokinetics").

Geriatric patients

In elderly patients, dose reduction of pregabalin may be necessary due to impaired renal function (see section "Special precautions").

Children

The safety and efficacy of pregabalin in pediatric patients (under 18 years of age) have not been established. The available information is presented in section "Adverse reactions" as well as in sections "Pharmacodynamics" and "Pharmacokinetics"; however, based on this information, no dosing recommendations can be provided for this patient population.

Overdose

Since the drug has been marketed, the most commonly reported adverse reactions in cases of pregabalin overdose have been somnolence, confusion, agitation, and restlessness. Seizures have also been reported.

Coma has been reported rarely.

Management of pregabalin overdose consists of general supportive measures and, if necessary, hemodialysis (see section "Dosage and administration", table).

Adverse Reactions

In the clinical development program for pregabalin, over 8,900 patients received the drug, including 5,600 participants in double-blind, placebo-controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally mild to moderate in severity. In all controlled trials, the discontinuation rate due to adverse reactions was 12% among patients receiving pregabalin and 5% among those receiving placebo. The most common adverse reactions leading to discontinuation of the study drug in the pregabalin group were dizziness and somnolence.

Below is a list of all adverse reactions occurring more frequently than with placebo and in more than one patient. These adverse reactions are categorized by system organ 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); frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

During treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, CNS-related adverse reactions, and particularly somnolence, was increased.

The adverse reactions listed below may be related to the underlying disease and/or concomitant use of other medicinal products.

Additional adverse reactions reported after marketing of the drug are indicated in italics in the list below.

Infections and infestations: common – nasopharyngitis.

Immune system disorders: uncommon – hypersensitivity; rare – angioneurotic edema, allergic reactions, anaphylactoid reactions.

Blood and lymphatic system disorders: uncommon – neutropenia.

Metabolism and nutrition disorders: common – increased appetite; uncommon – anorexia, hypoglycemia.

Psychiatric disorders: common – euphoric mood, confusion, irritability, disorientation, insomnia, decreased libido; uncommon – hallucinations, panic attacks, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood changes, depersonalization, difficulty in word finding, pathological dreams, increased libido, anorgasmia, apathy; rare – disinhibition, suicidal behavior, suicidal ideation; frequency not known – drug dependence.

Nervous system disorders: very common – dizziness, somnolence, headache; common – ataxia, coordination disorder, tremor, dysarthria, amnesia, memory impairment, attention disturbance, paresthesia, hypoesthesia, sedation, balance disorder, lethargy; uncommon – syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive dysfunction, worsening of mental status, speech disorder, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, apathy, perioral paresthesia; rare – seizures, parosmia, hypokinesia, dysgraphia, parkinsonism, hypalgesia, dependence, cerebellar syndrome, cogwheel rigidity, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain-Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders.

Eye disorders: common – blurred vision, diplopia, conjunctivitis; uncommon – peripheral vision loss, visual disturbance, eye swelling, visual field defect, decreased visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, blepharitis, accommodation disorder, subconjunctival hemorrhage, photophobia, retinal edema; rare – vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, brightness of vision, anisocoria, corneal ulceration, exophthalmos, extraocular muscle paralysis, iritis, keratoconjunctivitis, miosis, night blindness, ophthalmoplegia, optic nerve atrophy, optic disc edema, ptosis, uveitis.

Ear and labyrinth disorders: common – vertigo; uncommon – hyperacusis.

Cardiac disorders: uncommon – tachycardia, first-degree atrioventricular block, sinus bradycardia, congestive heart failure, arterial hypotension/hypertension, flushing, cold sensation in extremities; rare – prolongation of Q-T interval, sinus tachycardia, sinus arrhythmia.

Respiratory, thoracic and mediastinal disorders: common – pharyngolaryngeal pain; uncommon – dyspnea, epistaxis, cough, nasal congestion, rhinitis, snoring, dryness of nasal mucosa; rare – pulmonary edema, throat tightness, laryngospasm, apnea, atelectasis, bronchiolitis, hiccups, pulmonary fibrosis, yawning; frequency not known – respiratory depression.

Gastrointestinal disorders: common – vomiting, nausea, constipation, diarrhea, flatulence, abdominal distension, dry mouth, gastroenteritis; uncommon – gastroesophageal reflux disease, excessive salivation, oral hypoesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, rectal bleeding; rare – ascites, pancreatitis, tongue swelling, dysphagia, aphthous stomatitis, esophageal ulcer, periodontal abscess.

Hepatobiliary disorders: uncommon – elevated liver enzymes*; rare – jaundice; very rare – liver failure, hepatitis.

Skin and subcutaneous tissue disorders: common – pressure ulcers; uncommon – papular rash, urticaria, hyperhidrosis, pruritus, alopecia, dry skin, eczema, hirsutism, skin ulcers, vesiculobullous rash; rare – Stevens-Johnson syndrome, cold sweat, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail disorders, petechial rash, purpura, pustular rash, skin atrophy, skin necrosis, skin and subcutaneous nodules, toxic epidermal necrolysis (TEN).

Musculoskeletal and connective tissue disorders: common – muscle spasms, arthralgia, back pain, limb pain, neck spasms; uncommon – joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness; rare – rhabdomyolysis.

Renal and urinary disorders: uncommon – urinary incontinence, dysuria, albuminuria, hematuria, kidney stone formation, nephritis; rare – renal failure, oliguria, urinary retention, acute renal failure, glomerulonephritis, pyelonephritis.

Reproductive system and breast disorders: common – erectile dysfunction, impotence; uncommon – sexual dysfunction, ejaculation delay, dysmenorrhea, breast pain, leukorrhea, menorrhagia, metrorrhagia; rare – amenorrhea, breast discharge, breast enlargement, gynecomastia, cervicitis, balanitis, epididymitis.

General disorders and administration site conditions: common – peripheral edema, edema, gait disturbance, fall, feeling drunk, unusual sensations, fatigue; uncommon – generalized edema, facial swelling, chest tightness, pain, increased body temperature, thirst, chills, asthenia, general weakness, malaise, abscess, cellulitis, photosensitivity reactions; rare – granuloma, self-harm, retroperitoneal fibrosis, shock.

Investigations: common – weight increased; uncommon – increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, weight decreased; rare – decreased blood leukocyte count.

* Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

After discontinuation of short-term and long-term treatment with pregabalin, withdrawal symptoms were observed in some patients. Reported reactions included insomnia, headache, nausea, anxiety, diarrhea, flu-like symptoms, seizures, restlessness, depression, suicidal thoughts, pain, hyperhidrosis, and dizziness, indicating physical dependence. Patients should be informed of this at the beginning of therapy.

Regarding discontinuation of pregabalin after long-term treatment, data suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.

Children

The safety profile of pregabalin established in five studies involving pediatric patients with partial seizures with or without secondary generalization (a 12-week efficacy and safety study in patients aged 4 to 16 years, n=295; a 14-day efficacy and safety study in patients aged 1 month to 4 years, n=175; a pharmacokinetic and tolerability study, n=65; and two open-label, one-year safety studies, n=54 and n=431) was similar to that observed in adult epilepsy studies. The most common adverse events observed in the 12-week pregabalin treatment study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis. The most common adverse events during the 14-day pregabalin treatment study were somnolence, upper respiratory tract infections, and pyrexia (see sections "Pharmacodynamics", "Pharmacokinetics", and "Dosage and Administration").

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store in the original packaging.

No special storage conditions required.

Keep out of reach of children.

Packaging

14 capsules in a blister. 4 blisters in a carton.

Prescription status

Prescription only.

Manufacturer

Pharmaceutical Works "Polpharma" S.A., Poland.

Manufacturer's address and place of business

19 Pelplinska Street, 83-200 Starogard Gdanski, Poland.