Pregabalin asino

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Pregabalin Acino (Pregabalin Acino)

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 physicochemical properties: white hard gelatin capsules. The contents of the capsules are a 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 N02B F02.

Pharmacological Properties

Pharmacodynamics

Active substance — pregabalin, 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 medicinal product has been demonstrated in clinical studies 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 studied in 10 controlled clinical trials of up to 13 weeks' duration with a twice-daily dosing regimen and in trials of up to 8 weeks' duration with a three-times-daily regimen. Overall, the safety and efficacy profiles for twice-daily and three-times-daily dosing regimens were similar.

In clinical trials of up to 12 weeks' duration, in which the medicinal product was used for the treatment of neuropathic pain, reduction in both peripheral and central origin 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 group patients. 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 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 3 controlled clinical trials of 12 weeks' duration with twice-daily or three-times-daily dosing regimens. Overall, the safety and efficacy profiles for twice-daily and three-times-daily dosing 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 including 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 two 1-year open-label safety trials 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 epilepsy patients (see sections "Dosage and Administration", "Adverse Reactions", and "Pharmacokinetics").

In the 12-week placebo-controlled trial, 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. 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), 29.1% of patients receiving pregabalin at 2.5 mg/kg/day (p = 0.2600 compared to placebo), and 22.6% of those receiving placebo.

In the 14-day placebo-controlled trial, children (aged 1 month to 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, in the pregabalin 7 mg/kg/day group, 5.4 and 1.4 in the pregabalin 14 mg/kg/day group, and 2.9 and 2.3 in the placebo group. 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 in 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. 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 (for patients with newly diagnosed disease). Pregabalin was studied in one controlled clinical trial of 56 weeks' duration with a twice-daily dosing regimen. Pregabalin did not achieve comparable efficacy to lamotrigine, as assessed at 6 months using seizure freedom as the primary endpoint. Pregabalin and lamotrigine were similarly safe and well tolerated.

Generalized Anxiety Disorder

Pregabalin was studied in 6 controlled trials of 4–6 weeks' duration, one 8-week trial in 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 (4–8 weeks' duration), a ≥50% improvement in total HAM-A score from baseline to endpoint was observed in 52% of patients receiving pregabalin and in 38% of patients in the placebo group.

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

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). These trials included patients diagnosed with 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. The primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured on an 11-point rating scale) showed numerically greater improvement in patients receiving pregabalin compared to placebo, but this improvement did not achieve statistical significance. The most commonly reported adverse reactions in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics

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 fasting and reaches maximum plasma concentrations within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥90% and is dose-independent. At steady state, achieved after 24–48 hours of repeated administration, plasma concentrations are stable. The absorption rate of pregabalin is reduced when taken 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 does not have a clinically significant effect on the extent of absorption.

Distribution

Preclinical studies demonstrated 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 radiolabeled pregabalin, approximately 98% of the radioactivity was excreted in urine as unchanged pregabalin. The main metabolite, N-methylated derivative of pregabalin, accounted for 0.9% of the administered dose. During preclinical studies, no racemization of the S-enantiomer of pregabalin to the R-enantiomer was observed.

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 subsection "Renal Impairment" below).

Dosage 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 across the entire recommended dose range. The variability of pregabalin pharmacokinetics among patients is low (<20%). Pharmacokinetics after multiple dosing are predictable based on data from single-dose administration. Therefore, routine monitoring of plasma concentrations of pregabalin is not necessary.

Gender

Clinical trial 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 by hemodialysis (after 4 hours of hemodialysis, plasma concentration of pregabalin decreases by approximately 50%). Since the drug is primarily eliminated by the kidneys, dosage reduction is required for patients with renal impairment, and supplemental dosing is necessary after hemodialysis (see section "Dosage 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 predominantly unchanged in urine, hepatic impairment is unlikely to 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, 5, 10, and 15 mg/kg/day in a pharmacokinetic and tolerability study.

After oral administration of pregabalin to children under fasting conditions, the time to reach maximum plasma concentration was generally similar across all age groups, ranging from 0.5 to 2 hours after dosing.

Cmax and area under the concentration-time curve (AUC) values 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% higher body weight-adjusted clearance in these patients compared to those 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 demonstrated 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, with this relationship being 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 oral pregabalin clearance is consistent with age-related decline in creatinine clearance. Elderly patients with age-related renal impairment may require dose reduction of pregabalin (see section "Dosage and Administration", Table 1).

Breastfeeding

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 minimal effect on pregabalin pharmacokinetics. 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. Pregabalin Asino is indicated for the treatment of peripheral or central neuropathic pain in adults.

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

Generalized anxiety disorder. Pregabalin Asino 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 negligible 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. In in vivo studies, no clinically significant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol. Population pharmacokinetic analysis has shown that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate have no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and ethinylestradiol. Concomitant administration of pregabalin with oral contraceptives, norethisterone and 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, coma, and death 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 basic motor impairments caused by oxycodone.

Interactions in elderly patients. Specific pharmacodynamic interaction studies involving elderly volunteers have not 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 diabetic patients whose body weight has increased during pregabalin therapy may require adjustment of antidiabetic medication doses.

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

Severe skin adverse reactions (SSARs). Rare cases of SSARs, including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported during treatment with pregabalin; these reactions may be life-threatening or result in death. Patients should be informed of the possibility of these reactions when prescribed pregabalin and advised to closely monitor their skin. If signs or symptoms of SSARs, including SJS or TEN, appear, pregabalin should be discontinued immediately and alternative therapy considered (if required).

Dizziness, somnolence, loss of consciousness, confusion, and psychiatric disturbances. Pregabalin use has been associated with dizziness and somnolence, increasing the risk of trauma (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. Blurred vision occurred more frequently in patients receiving pregabalin than in those receiving placebo during controlled clinical trials. In most cases, this effect resolved with continued therapy. In clinical studies 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 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 with the addition of pregabalin to allow transition to pregabalin monotherapy.

Heart failure. Post-marketing reports have described cases of congestive heart failure in some patients treated with 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 condition may resolve after 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 additive effects of concomitant medications (e.g., antispastic agents) required for management of 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, those taking concomitant CNS depressants, and elderly patients are at higher risk of this serious adverse reaction. Dose adjustment 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 showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown. Post-marketing reports have described suicidal thoughts and behavior in patients treated with 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.

Patients (and caregivers) should seek medical help if signs of suicidal thoughts or behavior occur. Patients should be closely monitored for signs of suicidal thoughts and behavior, and appropriate treatment initiated if necessary. If a patient develops suicidal thoughts or behavior, discontinuation of pregabalin therapy may be considered.

Worsening of lower gastrointestinal tract function. Post-marketing reports have described worsening of lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) with pregabalin use, particularly when co-administered with medications that may cause constipation, 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"). In a case-control study of opioid users, an increased risk of opioid-related mortality was observed in patients receiving pregabalin 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]) and tended to increase at higher pregabalin doses (> 300 mg, aOR 2.55 [95% CI 1.24–5.06]).

Misuse, abuse, or dependence. Therapeutic doses of pregabalin may lead to drug dependence. Cases of misuse and abuse have been reported. Patients with a history of substance abuse are at higher risk of misuse, abuse, or dependence and should be treated with caution. A careful assessment of the risk of misuse, abuse, or dependence should be performed before prescribing pregabalin.

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

Withdrawal symptoms. Withdrawal symptoms have been observed in some patients after discontinuation of short- or long-term pregabalin therapy. Reported symptoms include insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness, suggesting drug dependence. The occurrence of withdrawal symptoms after stopping pregabalin may indicate drug dependence (see section "Adverse reactions"). This information should be communicated to patients before starting therapy.

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

Seizures, including epileptic status and generalized 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 depend on the dose.

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

Women of childbearing potential / contraception. Pregabalin use during the first trimester of pregnancy may cause major congenital malformations in the fetus. Pregabalin should not be used during pregnancy unless clearly necessary and 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 "Use during pregnancy or lactation").

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

Use during pregnancy or lactation

Women of childbearing potential / contraception

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

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) among liveborn or stillborn infants exposed to pregabalin during the first trimester compared to unexposed infants (5.9% vs. 4.1%).

The risk of MCMs in infants whose mothers took pregabalin during the first trimester of pregnancy was slightly higher compared to unexposed infants [adjusted prevalence ratio and 95% CI: 1.14 (0.96–1.35)] and compared to infants 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, eye, orofacial clefts, urinary tract, and genital malformations, although the number of such cases was small and estimates imprecise.

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

Lactation

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

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 receiving 600 mg/day, no effect on sperm motility was observed after 3 months of treatment.

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

Ability to influence driving and use of machines. Pregabalin may have a minor or moderate influence on the ability to drive and operate machinery. Pregabalin may cause dizziness and somnolence, thereby affecting the ability to drive and operate machinery. Therefore, patients should be advised to refrain from driving, operating complex machinery, or engaging in other potentially hazardous activities until they know how this medicinal product affects their ability to perform such activities.

Method of Administration and Dosage

Method of Administration

The medicinal product Pregabalin Asino is taken regardless of food intake.

This medicinal product is intended for oral use only.

Dosage

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

Neuropathic pain. Pregabalin therapy may be initiated at a dose of 150 mg per day, divided into 2 or 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. Pregabalin therapy may be initiated at a dose of 150 mg per day, divided into 2 or 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 further 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 reassessed.

Pregabalin therapy 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 administration, the dose may be increased to 450 mg per day. After an additional week, the dose may be increased to the maximum of 600 mg per day.

Fibromyalgia. The recommended dose of the drug for the treatment of fibromyalgia is 300 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 in whom a dose of 300 mg per day is insufficiently effective, the dose may be increased to 225 mg twice daily (450 mg per day). Although a study has evaluated the use of a 600 mg per day dose, there is no evidence that this dose provides additional benefit; moreover, patients tolerated this dose less well. Considering dose-dependent adverse reactions, doses above 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 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 in patients with renal impairment should be individually adjusted as indicated in the table below, based on creatinine clearance (CLcr) calculated using the following formula:

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

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	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 schedule to obtain the single dose (mg/dose).

** Administer pregabalin at the appropriate dosage.

• Additional dose means an extra single dose.

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

Geriatric patients. In elderly patients, dose reduction of pregabalin may be necessary due to impaired renal function (see section "Dosage and administration").

Children. The safety and efficacy of the medicinal product Pregabalin Asino in children (under 18 years of age) have not been established. Available data are presented in the sections "Adverse reactions", "Pharmacodynamics" and "Pharmacokin游戏副本", however, based on these data, no dosage recommendations can be provided for this patient population.

Overdose. Post-marketing reports indicate that the most commonly reported symptoms of pregabalin overdose were somnolence, confusion, agitation and restlessness. Seizures have also been reported.

Coma has been observed rarely.

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

Adverse Reactions

In the clinical development program for pregabalin, over 8900 patients received the drug, including 5600 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 studies, the discontinuation rate due to adverse reactions was 12% among patients taking pregabalin and 5% among those receiving placebo. The most common adverse reactions leading to discontinuation of pregabalin were dizziness and somnolence.

Below are listed all adverse reactions occurring more frequently than with placebo and in more than one patient, 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 based on available data). Within each frequency category, adverse effects are listed in descending order of severity.

The listed 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 and especially somnolence (see section "Special Warnings and Precautions for Use").

Additional adverse reactions reported after marketing authorization are 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, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition, suicidal behaviour, suicidal ideation.

Frequency not known: drug dependence.

Nervous system disorders

Very common: dizziness, somnolence, headache.

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

Uncommon: syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive dysfunction, 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, eye hemorrhage, photophobia, retinal edema.

Rare: vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcer, exophthalmos, oculomotor 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: prolonged QT interval, 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, 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 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, toxic epidermal necrolysis, 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 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, falls, feeling drunk, unusual sensations, increased fatigue.

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

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

Investigations

Common: weight gain.

Uncommon: increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, weight loss.

Rare: decreased blood leukocyte count.

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

In some patients, symptoms of withdrawal have been observed after discontinuation of short-term or long-term pregabalin therapy. Reported symptoms 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 withdrawal after prolonged pregabalin use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.

Paediatric population. The safety profile of pregabalin established in five studies involving paediatric patients with partial seizures with or without secondary generalization (a 12-week efficacy and safety study in patients aged 4 to 16 years, n = 295; a 14-day efficacy and safety study in patients aged 1 month to 4 years, n = 175; a pharmacokinetic and tolerability study, n = 65; two open-label, one-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 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, pharmacists, patients, and 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.

In case of adverse reactions or questions regarding the safety and efficacy of the medicine, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel./Fax: +38 044 281 2333.

Shelf life. 3 years.

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

Packaging. 10 capsules per blister; 1, 3 or 6 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. LLC "Pharma Start".

Manufacturer's address and place of business. 8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.