Pregabalin-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Pregabalin-ZN (Pregabalin-ZN)

Composition:

Active ingredient: pregabalin;

1 hard capsule contains pregabalin 75 mg or 150 mg;

Excipients: lactose monohydrate; pregelatinized (granulated) starch, magnesium stearate, titanium dioxide (E 171), gelatin, erythrosine (E 127), quinoline yellow (E 104) (for 75 mg capsules), indigo carmine (E 132) (for 150 mg capsules).

Medicinal form. Hard capsules.

Main physicochemical properties:

• 75 mg capsules: hard gelatin capsules № 4 with a white body and yellow cap, with hemispherical ends. The contents of the capsules are an almost white powder.
• 150 mg capsules: hard gelatin capsules № 1 with a white body and red cap, with hemispherical ends. The contents of the capsules are an almost white powder.

Pharmacotherapeutic group.

Antiepileptic drugs, other antiepileptic drugs. ATC code N03AX16.

Pharmacological Properties

Pharmacodynamics

The active substance is pregabalin, a structural analogue of gamma-aminobutyric acid ((S)-3-(aminomethyl)-5-methylhexanoic 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

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

Pregabalin has been studied in 10 controlled clinical trials lasting up to 13 weeks with a twice-daily dosing regimen and in trials lasting up to 8 weeks with a three-times-daily regimen. Overall, the safety and efficacy profiles of 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 maintained throughout the treatment period.

In controlled clinical trials of peripheral neuropathic pain, 35% of patients receiving pregabalin and 18% of patients receiving placebo experienced a 50% improvement on the pain rating scale. 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 somnolipenia, the proportion of responders was 48% in the pregabalin group and 16% in the placebo group.

In a controlled clinical trial of central 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 twice-daily or three-times-daily dosing regimens. Overall, the safety and efficacy profiles of 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 in 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 in 295 children aged 4 to 16 years, a 14-day placebo-controlled study in 175 children aged 1 month to less than 4 years, aimed at 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, respectively, 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 "Dosage and administration", "Adverse reactions", and "Pharmacokinetics").

In the 12-week placebo-controlled study, children (aged 4 to 16 years) were administered pregabalin at 2.5 mg/kg/day (maximum 150 mg/day), pregabalin at 0.0 mg/kg/day (maximum 600 mg/day), or placebo. A reduction of at least 50% in partial seizures compared to baseline was observed in 40.6% of patients receiving pregabalin at 10 mg/kg/day (p = 0.0068 compared to placebo), in 29.1% of patients receiving pregabalin at 2.5 mg/kg/day (p = 0.2600 compared to placebo), and in 22.6% of those receiving placebo.

In the 14-day placebo-controlled study, children (aged 1 month to less than 4 years) were administered pregabalin at 7 mg/kg/day, pregabalin at 14 mg/kg/day, or placebo. Median daily seizure frequency at baseline and at the final visit was 4.7 and 3.8, respectively, with pregabalin 7 mg/kg/day; 5.4 and 1.4 with pregabalin 14 mg/kg/day; and 2.9 and 2.3 with 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 demonstrate 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 patients aged 5 to 16 years) received pregabalin at 5 mg/kg/day (maximum 300 mg/day), pregabalin at 10 mg/kg/day (maximum 600 mg/day), or placebo as adjunctive therapy. A reduction of at least 50% 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. When pregabalin was used, equivalent efficacy compared to lamotrigine was not achieved based on the primary endpoint—seizure freedom at 6 months. 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), improvement of at least 50% in the 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% of patients in the placebo group. Visual field changes were detected 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 in one 6-week randomized withdrawal trial (F2). Patients enrolled in these trials had a diagnosis of fibromyalgia based on American College of Rheumatology criteria (widespread pain lasting at least 3 months and pain present in 11 or more of 18 specific tender points). 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 children aged 12–17 years with fibromyalgia who received pregabalin at doses of 75–450 mg/day. Based on the primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured using an 11-point rating scale), numerically greater improvement was observed in patients receiving pregabalin compared to those receiving placebo, but this improvement did not reach statistical significance. The most common adverse reactions observed 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

Pharmacokinetic parameters of pregabalin at steady state were 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, reaching peak plasma concentrations within 1 hour after single or multiple doses. The calculated oral bioavailability of pregabalin is ≥ 90% and is dose-independent. At steady state, achieved after 24–48 hours of multiple dosing. The rate of pregabalin absorption is reduced when administered with food, resulting in approximately a 25–30% decrease in maximum concentration (Cmax) and prolongation of tmax to approximately 2.5 hours. However, administration of pregabalin with food did not have a clinically significant effect on the extent of absorption.

Distribution

Preclinical studies have shown that pregabalin crosses the blood-brain barrier in mice, rats, and monkeys. It has been established that pregabalin crosses the placenta in rats and is excreted in the milk of lactating rats. In humans, the 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 the radioactivity was excreted in urine as unchanged pregabalin. The fraction of the N-methylated metabolite of pregabalin—the main metabolite detected in urine—was 0.9% of the administered dose. During preclinical studies, no racemization of the S-enantiomer of pregabalin to the R-enantiomer occurred.

Excretion

Pregabalin is eliminated from systemic circulation unchanged, primarily via the kidneys. The mean elimination half-life of pregabalin is 6.3 hours. Plasma and renal clearance of pregabalin are directly proportional to creatinine clearance (see section "Pharmacokinetics. Renal impairment").

Dose adjustment is required for patients with renal impairment or patients undergoing hemodialysis (see section "Dosage and administration", table).

Linearity/Non-linearity

The pharmacokinetics of pregabalin are linear over the entire recommended dose range. The inter-patient variability in pregabalin pharmacokinetics is low (< 20%). Pharmacokinetics after multiple dosing are predictable based on data obtained after single-dose administration. Therefore, routine monitoring of plasma concentrations of pregabalin is not necessary.

Gender

Clinical study results indicate no clinically significant effect of gender on plasma concentrations of pregabalin.

Renal impairment

Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (after 4 hours of hemodialysis, plasma concentration of pregabalin decreases by approximately 50%). Since the drug is primarily eliminated by the kidneys, dose reduction is required for patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Dos游戏副本 and administration", table).

Hepatic impairment

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is excreted in urine predominantly unchanged, it is unlikely that hepatic impairment would have a significant effect on plasma concentrations of pregabalin.

Children

The pharmacokinetics of pregabalin were evaluated in children with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years, and 12 to 16 years) receiving doses of 2.5 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 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 administration.

Cmax and area under the concentration-time curve (AUC) values of pregabalin increased linearly with dose in each age group. In children with body weight less than 30 kg, AUC values were 30% lower, due to a 43% increase in body weight-corrected clearance in these patients compared to patients with body weight ≥ 30 kg.

The terminal 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 in patients under 3 months of age have not been studied (see sections "Dosage and administration", "Adverse reactions", and "Pharmacodynamics").

Elderly patients

Pregabalin clearance tends to decrease with age. This reduction in pregabalin clearance with oral administration is consistent with age-related decreases in creatinine clearance. Elderly patients with age-related renal impairment may require dose reduction of pregabalin (see section "Dosage and administration", table).

Lactation

The pharmacokinetics of pregabalin were evaluated in 10 breastfeeding women who received pregabalin 150 mg every 12 hours (daily dose 300 mg), at least 12 weeks postpartum. Breastfeeding did not affect or had a negligible effect on the pharmacokinetics of pregabalin. Pregabalin was excreted into breast milk, with average steady-state concentrations in breast milk being approximately 76% of maternal plasma concentrations. The calculated infant dose received via breast milk (assuming average milk intake of 150 mL/kg/day) from a woman taking pregabalin at a dose of 300 mg/day or 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 mother's total daily dose on a mg/kg basis.

Clinical characteristics.

Indications.

Neuropathic pain.

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

Epilepsy.

Pregabalin is indicated in adults as adjunctive therapy for partial seizures with or without secondary generalization.

Generalized anxiety disorder.

Pregabalin is indicated for the treatment of generalized anxiety disorder in adults.

Fibromyalgia.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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

In vivo studies and population pharmacokinetic analysis.

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 demonstrated that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate have no clinically relevant effect on pregabalin clearance.

Oral contraceptives, norethisterone and/or ethinylestradiol.

Concomitant administration of pregabalin with 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 surveillance period, cases of respiratory depression, coma, and death have been reported in patients who took pregabalin together with opioids and/or other medicinal products that depress CNS function. Pregabalin is likely to enhance cognitive and basic motor function impairment caused by oxycodone.

Interactions in elderly patients.

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

Special precautions for use.

Patients with diabetes mellitus.

According to current clinical practice, some patients with diabetes mellitus whose body weight has increased during pregabalin therapy may require adjustment of their antidiabetic medication doses.

Hypersensitivity reactions.

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

Severe cutaneous adverse reactions.

Rare cases of severe cutaneous adverse reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis, have been reported during pregabalin treatment. These reactions may be life-threatening or fatal. When prescribing the medicinal product, patients should be informed about 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 treatment 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 risk of traumatic events (e.g., falls) in elderly patients. Post-marketing reports have also described cases of loss of consciousness, confusion, and psychiatric disturbances. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of this medicinal product.

Visual disorders.

During controlled clinical trials, blurred vision was reported more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this effect resolved with continued therapy. In clinical trials involving ophthalmological examinations, the incidence of decreased visual acuity and visual field changes was higher in patients treated with pregabalin compared to placebo; however, the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacodynamics").

Post-marketing reports have also described ocular adverse reactions, including vision loss, blurred vision, or other visual acuity changes, many of which were transient. These ocular symptoms may resolve or diminish after discontinuation of pregabalin.

Renal impairment.

Cases of renal impairment, sometimes reversible after discontinuation of pregabalin, have been reported.

Discontinuation of concomitant antiepileptic drugs.

There is insufficient data on whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved by adding pregabalin, in order to switch to pregabalin monotherapy.

Withdrawal symptoms.

Withdrawal symptoms have been observed in some patients after discontinuation of short-term or long-term pregabalin therapy. Reported events include insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness, suggesting physical dependence. This information should be communicated to patients prior to initiating therapy.

Seizures, including status epilepticus and major convulsive seizures, may occur during pregabalin therapy or shortly after its discontinuation.

Data on withdrawal after long-term use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.

Heart failure.

Post-marketing reports have described cases of heart failure in some patients receiving pregabalin. This reaction was mostly observed during treatment of neuropathic pain in elderly patients with pre-existing cardiovascular disorders. Pregabalin should be used with caution in such patients. This effect 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 (especially somnolence), was increased. This may be related to the additive effects of concomitant medications (e.g., antispastic agents) required for managing this condition. This should be taken into account when prescribing pregabalin for this indication.

Respiratory depression.

Cases of severe respiratory depression have been reported with pregabalin use. Patients with impaired respiratory function, respiratory or neurological disorders, renal impairment, concomitant use of CNS depressants, and elderly patients may be at higher risk for this serious adverse reaction. Dose adjustments may be required for these patients.

Suicidal thoughts and behavior.

Cases of suicidal thoughts and behavior have been reported in patients receiving antiepileptic drugs for various indications. A meta-analysis of data from randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude an increased risk with pregabalin use.

Therefore, patients should be carefully monitored for signs of suicidal thoughts and behavior, and appropriate treatment should be considered. If signs of suicidal thoughts or behavior occur, patients (and caregivers) should seek immediate medical help.

Worsening of lower gastrointestinal tract function.

Post-marketing reports have described events related to worsening of lower gastrointestinal tract function (such as intestinal obstruction, paralytic ileus, constipation) with pregabalin use, particularly when used concomitantly with medications that may cause constipation, such as opioid analgesics. When pregabalin is used together 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 CNS depression (see section "Interaction with other medicinal products and other forms of interaction"). In a case–control study of individuals using opioids, an increased risk of opioid-related mortality was observed in patients receiving pregabalin concomitantly with an opioid 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]) with a trend toward higher risk at higher pregabalin doses (> 300 mg, aOR 2.55 [95% CI, 1.24–5.06]).

Misuse, abuse, or dependence.

Cases of misuse, abuse, and dependence have been reported. The drug should be used with caution in patients with a history of substance abuse. Patients should be monitored for signs of misuse, abuse, or dependence on pregabalin (cases of addiction, dose escalation, and drug-seeking behavior have been reported).

Encephalopathy.

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

Lactose intolerance.

The medicinal product contains lactose. If a patient has known intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Women of reproductive potential/contraception in women and men.

Since the potential risk to humans is unknown, women of reproductive potential should use effective contraception.

Pregnancy.

Adequate data on pregabalin use in pregnant women are lacking.

Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

The medicinal product should not be used during pregnancy unless clearly necessary (when the benefit to the mother clearly outweighs the potential risk to the fetus).

Breastfeeding.

A small amount of pregabalin has been detected in breast milk. Women should be informed that breastfeeding is not recommended during pregabalin use.

Fertility.

Clinical data on the effect of pregabalin on female fertility are lacking.

In a clinical study assessing the effect of pregabalin on sperm motility in healthy male volunteers, pregabalin was administered at a dose of 600 mg/day. After 3 months of treatment, no effect on sperm motility was observed.

In fertility studies in female rats, adverse effects on reproductive function were observed. In male rat fertility studies, adverse effects on reproductive function and development were observed. The clinical relevance of these findings is unknown.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

Pregabalin may have a negligible or moderate effect on the ability to drive vehicles or operate machinery. Pregabalin may cause dizziness and somnolence, thereby affecting the ability to drive vehicles or operate machinery. Therefore, patients should be advised to refrain from driving vehicles, operating complex machinery, or engaging in other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform such activities.

Method of administration and dosage.

Method of administration.

The medicinal product is taken independently of food intake.

This medicinal product is intended for oral use only.

Dosage.

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

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 doses, may range from 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 ranges from 300 to 450 mg per day. Treatment should be initiated with 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 who do not achieve sufficient benefit with a dose of 300 mg per day, the dose may be increased to 225 mg twice daily (450 mg per day). Although a study evaluated 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. Given the dose-dependent adverse reactions, doses exceeding 450 mg per day are not recommended. Since pregabalin 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 precautions" and "Adverse reactions").

Renal impairment.

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

CLcr (mL/min) = [	1.23 × (140 – age (years) × body weight (kg))	] (× 0.85 for females)
	plasma creatinine level (mmol/L)

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 procedure (see table).

Adjustment of pregabalin dosage according to renal function.

Creatinine clearance (CLcr), (mL/min)	Total daily dose of pregabalin*		Dosing regimen
	Initial dose (mg/day)	Maximum dose (mg/day)
≥ 60	150	600	Twice or three times daily
≥ 30 — < 60	75	300	Twice or three times daily
≥ 15 — < 30	25–50	150	Once or twice daily
< 15	25	75	Once daily
Supplemental dose after hemodialysis (mg)	25	100	Single dose**

* 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 for patients with hepatic dysfunction (see section "Pharmacokinetics").

Elderly patients.

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

Children.

The safety and efficacy of the medicinal product in children (under 18 years of age) have not been established. The currently available information is presented in the section "Adverse reactions" as well as in the 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 following pregabalin overdose have been somnolence, confusion, agitation, and restlessness. Seizures have also been reported.

Coma has been reported rarely.

Treatment of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis (see section "Method of administration and dosage", table).

Adverse Reactions

In the clinical development program for pregabalin, over 8900 patients received the drug, including 5600 patients who participated 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 study medication in the pregabalin group were dizziness and somnolence.

Below are listed 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 (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse effects are listed in order of decreasing severity.

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

During treatment of central neuropathic pain due to spinal cord injury, the overall frequency of adverse reactions increased, particularly CNS-related adverse reactions such as somnolence (see section "Dosage and Administration").

Additional adverse reactions reported post-marketing are listed below and indicated in italics.

Infections and infestations.

Common: nasopharyngitis.

Blood and lymphatic system disorders.

Uncommon: neutropenia.

Immune system disorders.

Uncommon: hypersensitivity.

Rare: angioedema, allergic reactions, anaphylactoid reactions.

Metabolism and nutrition disorders.

Common: increased appetite.

Uncommon: loss of appetite, 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 alterations, depersonalization, difficulty in word finding, abnormal dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition.

Nervous system disorders.

Very common: dizziness, somnolence, headache.

Common: ataxia, coordination disorder, tremor, dysarthria, amnesia, memory impairment, attention disturbance, paresthesia, hypesthesia, sedation, balance disorder, lethargy.

Uncommon: syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive impairment, psychiatric disturbance, speech disorders, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, apathy, perioral paresthesia, myoclonus.

Rare: seizures, parosmia, hypokinesia, dysphagia, hypalgesia, dependence, cerebellar syndrome, cogwheel rigidity, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain–Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders, parkinsonism.

Eye disorders.

Common: blurred vision, diplopia, conjunctivitis.

Uncommon: peripheral vision loss, visual disturbance, eye swelling, visual field defects, decreased visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, blepharitis, accommodation disorder, ocular hemorrhage, photophobia, retinal edema.

Rare: vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcer, 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.

Rare: QT interval prolongation, sinus tachycardia, sinus arrhythmia.

Vascular disorders.

Uncommon: arterial hypotension, arterial hypertension, flushing, hyperemia, cold extremities.

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, hiccup, 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, hypersalivation, oral hypoaesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, tongue swelling, rectal hemorrhage.

Rare: ascites, pancreatitis, tongue swelling, dysphagia, aphthous stomatitis, esophageal ulcer, periodontal abscess.

Hepatobiliary disorders.

Uncommon: increased liver enzymes*.

Rare: jaundice.

Very rare: hepatic 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: toxic epidermal necrolysis, 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.

Musculoskeletal and connective tissue disorders.

Common: muscle spasms, arthralgia, back pain, limb pain, neck muscle 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, galactorrhea, 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, hot flushes, thirst, chills, malaise, weakness, abscess, lipodermatitis, 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).

In some patients, withdrawal symptoms have been observed after discontinuation of short-term or long-term pregabalin therapy. Reported reactions include insomnia, headache, nausea, anxiety, diarrhea, flu-like symptoms, seizures, restlessness, depression, suicidal thoughts, pain, hyperhidrosis, and dizziness, indicating physical dependence. This information should be communicated to the patient prior to initiating therapy.

Data on pregabalin discontinuation after long-term use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.

Pediatric population. 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 less than 4 years, n = 175; a pharmacokinetic and tolerability study, n = 65; and two open-label, 1-year safety studies, n = 54 and n = 431) was similar to that observed in adult epilepsy studies. The most commonly reported adverse events in the 12-week pregabalin treatment study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis. The most commonly reported adverse events in the 14-day pregabalin treatment study were somnolence, upper respiratory tract infections, and pyrexia (see sections "Dosage and Administration", "Pharmacodynamics", and "Pharmacokinetics").

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 hard capsules in a blister; 2, 3, or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorovia Narodu".

Manufacturer's address and location of operations.

41 Kulikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.