Neogabin 150

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEOGABIN 75 (NEOGABIN 75) NEOGABIN 150 (NEOGABIN 150)

Composition:

Active substance: pregabalin;

1 capsule contains 75 mg or 150 mg of pregabalin;

Excipients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate, talc; hard gelatin capsule: gelatin, titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physico-chemical properties: hard gelatin capsules of white color. The contents of the capsules are white or almost white powder. The presence of compacted columns or lumps which disintegrate upon pressure is acceptable.

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

ATC code N02BF02.

Pharmacological Properties.

Pharmacodynamics.

Active substance – pregabalin, a derivative 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.

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

Pregabalin was evaluated 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, safety and efficacy profiles were similar for both dosing regimens.

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

In controlled clinical trials of 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 placebo-treated patients. Among patients who experienced somnolens, 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, safety and efficacy profiles were similar for both dosing regimens.

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

Children.

The efficacy and safety of pregabalin as adjunctive therapy in the treatment of 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 observed in adults. Results from a 12-week placebo-controlled study involving 295 children aged 4 to 16 years and a 14-day placebo-controlled study involving 175 children aged 1 month to less than 4 years, designed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, as well as 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 were observed more frequently in children than in adult patients with epilepsy (see sections "Pharmacokinetics", "Posology and method of administration", and "Adverse reactions").

In the 12-week placebo-controlled study, children (aged 4 to 16 years) received pregabalin at 2.5 mg/kg/day (maximum 150 mg/day), pregabalin at 10 mg/kg/day (maximum 600 mg/day), or placebo. At least a 50% reduction in partial seizures compared to 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 patients receiving placebo.

In the 14-day placebo-controlled study, children (aged 1 month to less than 4 years) received 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 7 mg/kg/day; 5.4 and 1.4 for pregabalin 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.

In a 12-week placebo-controlled trial involving 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), 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. When pregabalin was used, it did not achieve the same level of efficacy as lamotrigine, based on a comparative assessment at 6 months using the primary endpoint of seizure freedom. However, 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 the first week of treatment with pregabalin.

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

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. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundus examination with dilated pupils) were performed in over 3600 patients as part of 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 detected 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 with fibromyalgia were enrolled 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 a reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global impression and a questionnaire assessing the impact of fibromyalgia on quality of life.

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. The primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured on an 11-point rating scale) showed improvement in patients receiving pregabalin compared to those receiving placebo, but this improvement was not statistically significant. The most common adverse reactions observed in the trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics.

It is known that 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 and reaches maximum plasma concentrations within 1 hour after single and multiple doses. The calculated oral bioavailability of pregabalin is 90% and does not depend on dose. Steady-state concentrations are achieved within 24–48 hours after multiple dosing. The rate of pregabalin absorption is reduced when administered with food, resulting in a decrease of approximately 25–30% in maximum concentration (Cmax) and a delay in time to maximum concentration (tmax) by 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 demonstrated that pregabalin readily crosses the blood-brain barrier, as well as the placenta, and is excreted into breast milk during lactation. 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 the 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. Racemization of the S-enantiomer to the R-enantiomer does not occur.

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 (see section "Posology and method of administration").

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, therapeutic drug monitoring of plasma pregabalin concentrations is not necessary.

Gender.

Available data indicate 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 concentrations of pregabalin decrease by approximately 50%). Since renal excretion is the main route of elimination of pregabalin, dose reduction is required for patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Posology and method of administration").

Hepatic impairment.

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes negligible metabolism and is primarily excreted unchanged in urine, it is unlikely that hepatic impairment would significantly affect 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) at 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 (tmax) 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 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-corrected clearance in these patients compared to patients with body weight ≥30 kg.

The terminal elimination half-life of pregabalin averaged 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 "Posology and method of administration", "Adverse reactions", and "Pharmacodynamics").

Elderly patients.

It is known that pregabalin clearance tends to decrease with age. This reduction in oral pregabalin clearance is consistent with the age-related decline in creatinine clearance. Patients with age-related renal impairment may require dose reduction.

Lactation.

The pharmacokinetics of pregabalin administered at a dose of 150 mg every 12 hours (daily dose 300 mg) were evaluated in 10 breastfeeding women at least 12 weeks postpartum. Data indicate that breastfeeding had no effect or only a minor effect on the pharmacokinetics of pregabalin. Pregabalin was excreted into breast milk, with average steady-state concentrations in milk being 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 mother's total daily dose normalized to mg/kg.

Clinical characteristics.

Indications.

Neuropathic pain.

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

Epilepsy.

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

Generalized anxiety disorder.

Neogabin is indicated for the 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 urine, undergoes minimal metabolism in the human body (≤ 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 may cause pharmacokinetic drug interactions or be the object of such interactions.

In vivo studies and population pharmacokinetic analysis.

It is known from in vivo studies that there was no clinically significant pharmacokinetic interaction 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 have no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and/or ethinylestradiol.

Concomitant administration of pregabalin and oral contraceptives containing 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. Cases of respiratory depression, coma, and fatal outcomes have been reported in patients who concurrently used pregabalin with opioids and/or other medicinal products that depress CNS function, particularly in patients who abused such substances. Pregabalin is likely to enhance cognitive and gross motor function impairment caused by oxycodone.

Interaction in elderly patients.

Specific pharmacodynamic interaction studies involving elderly patients have not 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 diabetic patients who experience weight gain during pregabalin treatment may require adjustment of their antidiabetic medication doses.

Hypersensitivity reactions.

Hypersensitivity reactions, including cases of angioedema, have been reported. Pregabalin should be discontinued immediately if symptoms of angioedema occur, such as swelling of the face, perioral area, or upper airways.

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

Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of accidental injuries (e.g., falls) in elderly patients. Cases of loss of consciousness, confusion, and psychiatric disturbances have also been reported. Patients should therefore be advised to exercise caution until they are aware of the potential effects of the drug.

Visual disorders.

Transient blurred vision and other visual changes have been reported in patients taking pregabalin compared to those receiving placebo. In most cases, this phenomenon resolves with continued use of pregabalin.

Ophthalmological examinations in clinical studies have shown a higher incidence of decreased visual acuity and visual field changes in patients treated with pregabalin compared to placebo; however, the incidence of ocular fundus changes was higher in the placebo group.

Adverse effects on the eye, including vision loss, blurred vision, or other changes in visual acuity, have also been reported, most of which were transient. Discontinuation of pregabalin may help resolve or alleviate these ocular symptoms.

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 the discontinuation of concomitant antiepileptic drugs after seizure control is achieved when pregabalin is added to ongoing treatment, with the aim of switching to pregabalin monotherapy.

Withdrawal symptoms.

Withdrawal symptoms have been observed in some patients after discontinuation of short- and long-term pregabalin treatment. Reported symptoms 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 patients prior to initiating therapy.

If pregabalin treatment needs to be discontinued, it is recommended to do so gradually over at least 1 week, regardless of the indication (see section "Dosage and administration").

Seizures, including status epilepticus and generalized seizures, may occur during or shortly after discontinuation of pregabalin. Data on withdrawal after prolonged 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 patients taking pregabalin. This reaction was mostly observed during treatment of neuropathic pain in elderly patients with 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.

In the treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly CNS-related reactions and somnolence, was increased. This may be explained by an additive effect of concomitant medications (e.g., antispasmodics) required for managing this condition. This should be considered when prescribing pregabalin to such patients.

Respiratory depression.

Severe respiratory depression has 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 of this serious adverse reaction. Dose adjustments may be required for these patients (see section "Dosage and administration").

Suicidal thoughts and behavior.

Cases of suicidal thoughts and behavior have been observed in patients treated with antiepileptic drugs for various indications. Meta-analyses of randomized placebo-controlled trials of antiepileptic drugs have also shown a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown. Post-marketing reports have documented cases of suicidal thoughts and behavior in patients receiving pregabalin (see section "Adverse reactions"). An epidemiological study using a self-controlled design (comparing treatment periods with non-treatment periods in individual patients) demonstrated an increased risk of new-onset suicidal behavior and fatal outcomes due to suicide in patients receiving pregabalin.

Therefore, patients should be closely monitored for signs of suicidal thoughts and behavior, and appropriate treatment should be initiated if such signs occur. If suicidal thoughts or behavior develop, discontinuation of pregabalin therapy should be considered. Patients (and caregivers) should be informed of the need to seek medical help if signs of suicidal thoughts or behavior appear.

Worsening of lower gastrointestinal function.

Adverse events related to worsening of lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) have been reported following pregabalin use in combination with constipating agents such as opioid analgesics. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be implemented (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"). Clinical studies have shown an increased risk of fatal outcomes in patients taking pregabalin with opioids compared to those taking opioids alone. This increased risk was observed even with low doses of pregabalin, and a trend toward higher risk was seen with higher pregabalin doses.

Misuse, abuse, or dependence.

Therapeutic doses of pregabalin may lead to drug dependence. Cases of misuse, abuse, and dependence have been reported. The drug should be used cautiously in patients with a history of substance abuse. A careful assessment of the risk of misuse, abuse, or dependence should be conducted before prescribing pregabalin. Patients should be monitored for signs of misuse, abuse, or dependence (cases of drug-seeking behavior and dose escalation have been reported).

Encephalopathy.

Cases of encephalopathy have occurred predominantly in patients with comorbid conditions that may predispose to encephalopathy.

Severe skin adverse reactions.

Rare cases of severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which may be life-threatening or fatal, have been reported in association with pregabalin treatment. Patients should be informed of the signs and symptoms of these SSARs when the drug is prescribed, 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).

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").

The medicinal product contains less than 1 mmol of sodium (23 mg) per capsule, i.e., it is practically sodium-free. This information may be useful for patients on a low-sodium diet.

Use during pregnancy or breastfeeding.

Women of childbearing potential / contraceptive methods for women and men.

Women of childbearing potential must use effective contraception.

Pregnancy.

Reproductive toxicity has been observed in animal studies.

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 children (live or stillborn) exposed to pregabalin during the first trimester compared to unexposed children (5.9% vs. 4.1%).

The risk of MCMs in children whose mothers took pregabalin during the first trimester was slightly higher compared to unexposed children [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 nervous system malformations, eye defects, orofacial clefts, urinary tract malformations, and genital organ malformations, although the number of such cases was small and estimates imprecise.

The medicinal product Neogabin should not be used during pregnancy without strong medical justification (i.e., when benefit to the mother clearly outweighs the potential risk to the fetus).

Breastfeeding.

A small amount of pregabalin has been detected in human milk. Women should be advised that breastfeeding is not recommended during pregabalin treatment.

Fertility.

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

Data on the effect of pregabalin on sperm motility in men receiving a dose of 600 mg daily showed no effect after 3 months of treatment.

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

Effects on ability to drive and use machines.

Pregabalin may have a slight or moderate influence on the ability to drive and operate machinery. The drug may cause dizziness and somnolence and may affect the ability to drive a car or operate machinery. Patients should therefore be advised to refrain from driving or operating complex machinery until they know how the drug affects them.

Method of Administration and Dosage.

Method of Administration.

The medication can be administered regardless of food intake. This medicinal product is intended for oral use only.

Dosage.

The recommended dose of the drug ranges from 150 to 600 mg per day, divided into 2 or 3 doses.

Neuropathic Pain.

The initial dose of pregabalin is 150 mg per day, divided into 2 or 3** doses. Depending on the individual patient response and tolerability, the dose may be increased after 3–7 days to 300 mg per day, and if necessary, further increased to the maximum dose of 600 mg per day after another 7 days.

Epilepsy.

The initial dose of pregabalin is 150 mg per day, divided into 2 or 3** doses. Depending on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week. After another week, the dose may be increased to the maximum of 600 mg per day.

Generalized Anxiety Disorder.

The daily dose ranges from 150 to 600 mg, divided into two or three doses. The need for pregabalin treatment should be reviewed regularly.

Pregabalin treatment 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. During the following week, the dose may be increased to 450 mg per day. After another week, the dose may be increased to the maximum of 600 mg per day.

Fibromyalgia.

The usual dose of the medication for most patients is 300–450 mg per day. Treatment should be initiated at a dose of 75 mg twice daily (150 mg per day) and may be increased, depending on efficacy and tolerability, 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 studies have 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 the dose-dependent adverse reactions, doses exceeding 450 mg per day are not recommended. Since pregabalin is primarily eliminated by the kidneys, dosage adjustment is required in patients with impaired renal function.

Discontinuation of the Medication.

If pregabalin needs to be discontinued, it is recommended to gradually withdraw the medication over at least 1 week, regardless of the indication (see sections "Special Instructions" and "Adverse Reactions").

Patients with Renal Impairment.

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

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

Dosage adjustment of pregabalin depending on renal function status.

* The total daily dose (mg/day) should be divided into several administrations to obtain the number of milligrams per dose.

** Administer pregabalin at the appropriate dosage.

+ Additional dose – this is a single additional dose.

Patients with hepatic impairment.

Dose adjustment is not required for patients with hepatic impairment.

Use in elderly patients (over 65 years of age).

Dosage reduction of pregabalin may be necessary for elderly patients due to reduced renal function.

Children.

The safety and efficacy of pregabalin in children (under 18 years of age) have not been established. Available data are presented in the section "Adverse Reactions" as well as in the sections "Pharmacodynamics" and "Pharmacokinetics"; however, based on these data, no recommendations for use in this patient population can be provided.

Overdose.

The most commonly reported adverse reactions in cases of pregabalin overdose were somnolence, confusion, agitation, and restlessness.

Coma has been reported rarely. Seizures have also been reported.

Treatment of pregabalin overdose should include general supportive measures and, if necessary, hemodialysis.

Adverse Reactions

It is known that over 8900 patients received pregabalin in the clinical trial program, of whom 5600 were participants in double-blind, placebo-controlled studies. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally mild to moderate in severity. In all controlled trials, treatment discontinuation due to adverse reactions occurred in 12% of patients receiving pregabalin and in 5% of patients receiving placebo. The most common adverse reactions leading to discontinuation of pregabalin as the investigational drug were dizziness and somnolence.

Adverse reactions reported during pregabalin use are listed below by system organ class, with frequency categories defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data).

The listed adverse reactions may also be related to the underlying disease and/or concomitant medications. Data indicate that during treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions increased, particularly CNS-related adverse reactions and especially somnolence (see section "Special Warnings and Precautions for Use"). Adverse reactions identified after product marketing are listed below and are underlined.

Infections and infestations:
Common – nasopharyngitis.

Blood and lymphatic system disorders:
Uncommon – neutropenia.

Immune system disorders:
Uncommon – hypersensitivity; rare – angioedema, allergic reaction, anaphylactoid reactions.

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 swings, depersonalization, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy; rare – disinhibition, suicidal ideation and behavior; not known – drug dependence.

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, mental disorder, speech disorder, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, apathy, perioral paresthesia, myoclonus; rare – convulsions, parosmia, hypokinesia, dysgraphia, 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 defect, 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, visual brightness, anisocoria, corneal ulceration, exophthalmos, oculomotor nerve 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/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, hiccup, pulmonary fibrosis, yawning; frequency not known – respiratory depression.

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

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, toxic epidermal necrolysis, 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 cramps, arthralgia, back pain, limb pain, neck muscle spasms; uncommon – joint swelling, myalgia, muscle twitching, neck pain, muscle rigidity; 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 – ejaculation delay, sexual dysfunction, dysmenorrhea, breast pain, leukorrhea, menorrhagia, metrorrhagia; rare – amenorrhea, galactorrhea, breast hypertrophy, gynecomastia, cervicitis, balanitis, epididymitis.

General disorders and administration site conditions:
Common – peripheral edema, edema, gait disturbance, feeling drunk, falls, unusual sensations, fatigue; uncommon – generalized edema, facial swelling, chest tightness, pain, hot flushes, chills, malaise, asthenia, thirst, abscess, lipohypertrophy, photosensitivity reactions; rare – granuloma, self-harm, retroperitoneal fibrosis, shock.

Investigations:
Common – weight increased; uncommon – increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, decreased blood potassium, weight decreased; rare – decreased white blood cell count.

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

After discontinuation of short-term and long-term pregabalin treatment, withdrawal symptoms have been observed in some patients.

Reported reactions include: insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, convulsions, restlessness, depression, suicidal thoughts, pain, increased sweating, and dizziness, suggesting physical dependence.

Patients should be informed about this at the beginning of therapy.

Regarding discontinuation of pregabalin after long-term treatment, there are no data on the frequency and severity of withdrawal symptoms depending on duration of use and dosage.

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 "Pharmacodynamics", "Pharmacokinetics", and "Dosage and Administration").

Reporting 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.

Shelf life.

3 years.

Storage conditions.

Store out of reach and sight of children, in the original packaging, at a temperature not exceeding 25 °C.

Packaging.

10 capsules in a blister; 1, 3, or 6 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

TOV "Pharma Start".

Manufacturer's address and place of business.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse effects or questions regarding the safety of the medicinal product, please contact the Pharmacovigilance Department of TOV "ASINO UKRAINA" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +38 044 281 2333.