Kineiron

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KINEYRON (KINEYRON)

Composition:

Active substance: pregabalin;

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

Excipients: lactose monohydrate, maize starch, talc;

capsule shell for 75 mg: gelatin, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172), iron oxide black (E 172);

capsule shell for 150 mg: gelatin, titanium dioxide (E 171), sunset yellow (E 110);

capsule shell for 300 mg: gelatin, titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physicochemical properties:

hard gelatin capsules of cylindrical shape with an opaque white body and an opaque brown cap (for 75 mg dosage) or an opaque orange cap (for 150 mg dosage), or an opaque white cap (for 300 mg dosage), filled with white or almost white powder.

Pharmacotherapeutic group. Antiepileptic drugs, other antiepileptic agents.

ATC code N03AX16.

Pharmacological Properties.

Pharmacodynamics.

The active substance is pregabalin, which is a gamma-aminobutyric acid analogue [(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

The efficacy of the drug 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 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 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 in 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 trial involving 295 children aged 4 to 16 years and a 14-day placebo-controlled trial involving 175 children aged 1 month to 4 years, designed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and an open-label 1-year safety study involving 54 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 trial, children (aged 4 to 16 years) were administered 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 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 trial, children (aged 1 month to 4 years) were administered pregabalin at 7 mg/kg/day, pregabalin at 14 mg/kg/day, or placebo. The median daily seizure frequency at baseline and at the final visit was 4.7 and 3.8, respectively, for pregabalin at 7 mg/kg/day, 5.4 and 1.4 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 demonstrate improvement compared to placebo.

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 a 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 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 from baseline to endpoint in the total HAM-A score was observed in 52% of patients receiving pregabalin and in 38% of patients in the placebo group.

During controlled trials, blurred vision was observed more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this effect resolved with continued therapy. Ophthalmologic 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 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 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 for 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 involving 107 children aged 12–17 years with fibromyalgia who received pregabalin at doses of 75–450 mg/day. Based on the primary efficacy endpoint assessment (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 achieve 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 when administered on an empty stomach and reaches maximum plasma concentration (Cmax) within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥90% and is dose-independent. At steady state, equilibrium is reached within 24–48 hours after multiple dosing. The rate of pregabalin absorption is reduced when administered with food, resulting in approximately a 25–30% reduction in Cmax and prolongation of time to maximum concentration (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 into 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 derivative of pregabalin—the main metabolite detected in urine—was 0.9% of the administered dose. Racemization of the S-enantiomer of pregabalin to the R-enantiomer did not occur during preclinical studies.

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”).

Dosage adjustment is required for patients with renal impairment or patients on hemodialysis (see section “Dosage and administration”, Table 1).

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 from single-dose administration. Therefore, routine monitoring of plasma pregabalin concentrations is not necessary.

Gender

Clinical trial 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 pregabalin concentration decreases by approximately 50%). Since the drug is primarily eliminated by the kidneys, dosage reduction is required for patients with renal impairment, and a supplemental dose should be administered after hemodialysis (see section “Dosage and administration”, Table 1).

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 dysfunction would have a significant effect on plasma concentrations of pregabalin.

Children

Pregabalin pharmacokinetics 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, tmax was generally similar across all age groups and ranged from 0.5 to 2 hours after dosing.

Cmax and area under the concentration-time curve (AUC) of pregabalin 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 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.

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

Pregabalin pharmacokinetics 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 reduction in oral pregabalin clearance is consistent with age-related reduction in creatinine clearance. Elderly patients with age-related renal impairment may require dosage reduction of pregabalin (see section “Dosage and administration”, Table 1).

Lactation period

Pregabalin pharmacokinetics after administration at a dose of 150 mg every 12 hours (daily dose 300 mg) were evaluated in 10 breastfeeding women at least 12 weeks postpartum. Breastfeeding did not affect or had a negligible effect on pregabalin pharmacokinetics. 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 maternal total daily dose normalized to mg/kg.

Clinical characteristics.

Indications.

Neuropathic pain

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

Epilepsy

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

Generalized anxiety disorder

Kineiron 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 types of interactions.

Since pregabalin is predominantly excreted unchanged in urine, undergoes minimal metabolism in humans (≤ 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 pharmacokinetic interactions or be the object of such interactions.

In vivo studies and population pharmacokinetic analysis

Thus, in in vivo studies, no clinically significant pharmacokinetic interaction was 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 significant 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 medicinal product.

Medicinal products affecting the CNS

Pregabalin may potentiate the effects of ethanol and lorazepam. In the post-marketing surveillance period, cases of respiratory depression and coma have been reported in patients who took pregabalin together with opioids and/or other medicinal products that suppress CNS function. Pregabalin is likely to enhance cognitive and gross 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

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

Hypersensitivity reactions

Following the marketing of pregabalin, hypersensitivity reactions including angioedema have been reported. If symptoms of angioedema such as facial swelling, perioral swelling, or swelling of the upper airways occur, pregabalin should be discontinued immediately.

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 (falls) in elderly patients. Additionally, cases of loss of consciousness, confusion, and psychiatric disturbances have been reported post-marketing. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of this medicinal product.

Visual disorders

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

Post-marketing reports have also included ocular adverse reactions such as vision loss, blurred vision, or other changes in visual acuity, 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 currently insufficient data on whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved by adding pregabalin, in order to switch to monotherapy with pregabalin.

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, indicating physical dependence. This information should be communicated to the patient prior to initiating therapy.

Seizures, including epileptic status and generalized seizures, may occur during pregabalin therapy or shortly after its discontinuation.

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

Heart failure

Cases of congestive heart failure have been reported in some patients taking pregabalin following its marketing. 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 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 CNS-related adverse reactions such as somnolence, increased. This may be related to the additive effect of concomitant medications (e.g., antispastic agents) required for managing this condition. This factor should be considered when prescribing pregabalin for this indication.

Respiratory depression

Cases of severe respiratory depression associated with pregabalin use have been reported. Patients with impaired respiratory function, respiratory or neurological disorders, renal impairment, those receiving concomitant CNS depressants (including opioid-containing medications), and elderly patients may be at increased risk of this serious adverse reaction. Dose adjustment may be necessary for these patients (see section "Dosage and administration").

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 antiepileptic drug trials also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude the possibility of an increased risk with pregabalin use.

Therefore, patients should be closely 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.

Lower gastrointestinal tract dysfunction

Post-marketing reports have included events related to lower gastrointestinal tract dysfunction (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, patients receiving pregabalin together with an opioid had an increased risk of opioid-related mortality compared to those using opioids 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 a trend toward increased risk was observed at higher doses (> 300 mg, aOR 2.55 [95% CI, 1.24–5.06]).

Improper use, abuse, or dependence

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

Encephalopathy

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

Skin reactions

Serious skin adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be life-threatening or fatal, have been rarely reported in association with pregabalin treatment. Patients should be informed about the characteristic signs and symptoms, and skin reactions should be closely monitored during treatment. If symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative therapy considered (if necessary).

Lactose intolerance

Kineyron contains lactose. This medicinal product is contraindicated in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Women of childbearing potential / contraception for women and men

Use of pregabalin during the first trimester of pregnancy may cause serious congenital malformations in the unborn child. 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.

Pregnancy

Reproductive toxicity has been demonstrated in animal studies.

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

Breastfeeding period

A small amount of pregabalin has been detected in human breast milk. Women who are breastfeeding should be advised 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 daily. 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 significance of these findings is unknown.

Major congenital malformations

Clinical data from over 2700 pregnant women indicate that pregabalin use during the first trimester of pregnancy slightly increases the risk of major congenital malformations in infants (live or stillborn).

Analysis of specific malformations showed a higher risk of malformations of the nervous system, eyes, face (craniofacial region), urinary system, and genital organs; however, risk estimates may be imprecise due to the small number of cases and limited observation period.

Pregabalin should not be used during pregnancy unless clearly necessary (i.e., when benefit to the mother clearly outweighs the potential risk to the fetus).

Ability to affect reaction speed when driving or operating machinery.

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

Method of administration and dosage.

Method of administration

Kineiron should be 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 2–3 doses.

Neuropathic pain

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2–3 doses. Depending on 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 2–3 doses. Depending on 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 2–3 doses, 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 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 further 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 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 who do not achieve sufficient efficacy 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. Considering dose-dependent adverse reactions, doses exceeding 450 mg per day are not recommended. Since pregabalin is primarily eliminated by the kidneys, dosage adjustment is necessary in patients with impaired renal function.

Discontinuation of pregabalin

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

Renal impairment

Pregabalin is eliminated from systemic circulation unchanged, primarily via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage should be individually adjusted in patients with impaired renal function as indicated in Table 1, based on creatinine clearance (CLcr) calculated using the appropriate formula.

Pregabalin is effectively removed from plasma by hemodialysis (approximately 50% of the drug is removed 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 additional dose of the drug should be administered immediately after each 4-hour hemodialysis session (see Table 1).

Table 1

Dosage adjustment of pregabalin 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	2-3 times daily
≥ 30 – < 60	75	300	2-3 times daily
≥ 15 – < 30	25–50	150	1-2 times daily
< 15	25	75	once daily
Additional 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").

Children

The safety and efficacy of pregabalin in children under 18 years of age have not been established. Available information to date is presented in the 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

Following marketing of the drug, the most commonly reported adverse reactions associated with pregabalin overdose were somnolence, confusion, agitation, and restlessness. There have also been reports of seizures.

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 1).

Adverse Reactions

In the clinical development program for pregabalin, over 8900 patients received the drug, including 5600 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.

The following lists 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 reactions are listed in descending order of severity.

The reported adverse reactions 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 "Special Warnings and Precautions for Use").

Additional adverse reactions reported after marketing authorization 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 changes, depersonalization, word-finding difficulty, abnormal dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition, suicidal ideation and behavior.

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 dysfunction, mental disorder, speech disorder, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, apathy, perioral paresthesia, myoclonus.

Rare: seizures, parosmia, hypokinesia, dysphagia, hypalgesia, dependence, cerebellar syndrome, cogwheel syndrome, 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, reduced 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, brightness of vision, 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 sensation in 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, hiccups, pulmonary fibrosis, yawning.

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 bleeding.

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

Hepatobiliary disorders

Uncommon: increased liver enzymes*.

Rare: jaundice.

Very rare: liver failure, hepatitis.

Skin and subcutaneous tissue disorders

Common: pressure ulcers.

Uncommon: papular rash, urticaria, hyperhidrosis, itching, 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.

Musculoskeletal and connective tissue disorders

Common: muscle cramps, 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 delayed, 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, increased fatigue.

Uncommon: generalized edema, facial swelling, chest tightness, pain, hot flush, thirst, chills, general weakness, malaise, abscess, lipodermatitis, photosensitivity reactions.

Rare: granuloma, self-harm, retroperitoneal fibrosis, shock.

Laboratory 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 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.

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, nervousness, depression, suicidal thoughts, pain, hyperhidrosis, and dizziness, suggesting physical dependence. This information should be communicated to patients 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 four 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 a 1-year open-label safety study, n=54) was similar to that observed in adult epilepsy studies. The most commonly reported adverse events in the 12-week pregabalin therapy 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 therapy study were somnolence, upper respiratory tract infections, and pyrexia (see sections "Pharmacodynamics", "Pharmacokinetics", and "Dosage and Administration").

Reporting of adverse reactions. Reporting suspected adverse reactions after drug authorization is important. It allows continuous 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 at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

7 capsules in a blister, 2, 3, or 8 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

JSC "Tekhnolog".

Manufacturer's address and location of operations.

8 Staroprizhna Street, Uman, Cherkasy region, 20300, Ukraine.