Ligato

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIGATO® (LYGATO)

Composition:

Active substance: pregabalin;

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

Excipients: lactose monohydrate; corn starch; talc;

Capsule shell: gelatin, titanium dioxide (E 171), patent blue V (E 131) (for 75 mg capsules); gelatin, titanium dioxide (E 171) (for 150 mg capsules); titanium dioxide (E 171), erythrosine (E 127), carmoisine (E 122), brilliant blue FCF (E 133), gelatin (for 300 mg capsules).

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics:

75 mg hard capsules: blue-white hard gelatin capsules of size "4", filled with almost white powder;

150 mg hard capsules: white-white hard gelatin capsules of size "2", filled with almost white powder;

300 mg hard capsules: brown-white hard gelatin capsules of size "0", filled with almost white powder.

Pharmacotherapeutic group. Analgesics. Other analgesics and antipyretics. Gabapentinoids. Pregabalin. ATC code N02BF02.

Pharmacological Properties

Pharmacodynamics. The active substance is 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.

Clinical efficacy and safety

Neuropathic pain. Efficacy of the medicinal product 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, the safety and efficacy profiles of twice-daily and three-times-daily regimens were similar. In clinical trials lasting up to 12 weeks, in which pregabalin 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 of peripheral neuropathic pain, 35% of patients receiving pregabalin and 18% of patients receiving placebo experienced a 50% improvement on the pain rating scale. Among patients who did not experience somnolence, such improvement was observed in 33% of patients receiving pregabalin and 18% of placebo 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 7% of patients receiving placebo.

Epilepsy. Adjunctive therapy. Pregabalin was studied in 3 controlled clinical trials lasting 12 weeks with twice-daily or three-times-daily dosing regimens. Overall, the safety and efficacy profiles of twice-daily and three-times-daily regimens were similar. Reduction in seizure frequency was observed as early as the first week.

Children. The efficacy and safety of pregabalin as adjunctive therapy for epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study 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 results from two open-label safety studies lasting 1 year involving 54 and 431 children aged 3 months to 16 years with epilepsy indicate that adverse reactions such as pyrexia and upper respiratory tract infections occur more frequently in children than in adult patients with epilepsy (see sections “Pharmacokinetics”, “Dosage and administration”, and “Adverse reactions”). In the 12-week placebo-controlled 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. At least a 50% reduction 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), 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. Median daily seizure frequency at baseline and at the final visit was 4.7 and 3.8, respectively, with pregabalin at 7 mg/kg/day; 5.4 and 1.4 with pregabalin at 14 mg/kg/day; and 2.9 and 2.3 with placebo. Pregabalin at 14 mg/kg/day significantly reduced the logarithmically transformed frequency of partial seizures compared to placebo (p = 0.0223); pregabalin at 7 mg/kg/day did not demonstrate improvement compared to placebo. In a 12-week placebo-controlled 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) or 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 (for patients with newly diagnosed disease). Pregabalin was studied in one controlled clinical trial lasting 56 weeks with a twice-daily dosing regimen. Pregabalin did not demonstrate inferiority compared to lamotrigine based on the primary endpoint of seizure-free status assessed at 6 months. Pregabalin and lamotrigine were equally safe and well tolerated.

Generalized anxiety disorder. Pregabalin was studied in 6 controlled trials lasting 4–6 weeks, 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 (lasting 4–8 weeks), 52% of patients receiving pregabalin and 38% of patients in the placebo group experienced at least a 50% improvement in total HAM-A score from baseline to endpoint. 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 in controlled clinical trials. Among these patients, visual acuity worsened in 6.5% of patients in the pregabalin group and 4.8% in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and 11.7% of patients in the placebo group. Fundus changes were observed in 1.7% of patients receiving pregabalin and 2.1% of patients in the placebo group.

Fibromyalgia. The efficacy of pregabalin was established in one 14-week double-blind placebo-controlled multicenter trial (F1) and one 6-week randomized withdrawal trial (F2). These trials included patients diagnosed with fibromyalgia based on American College of Rheumatology criteria (widespread pain lasting at least 3 months and pain in at least 11 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 adolescents aged 12–17 years with fibromyalgia, who received pregabalin at doses of 75–450 mg/day. Based on the primary efficacy endpoint (change in overall pain intensity from baseline to week 15 measured on an 11-point rating scale), numerically greater improvement was observed in patients receiving pregabalin compared to those receiving placebo, but this improvement did not reach statistical significance. The most commonly observed adverse reactions in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics. 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 concentrations within 1 hour after single or multiple doses. The calculated oral bioavailability of pregabalin is ≥ 90% and is dose-independent. Steady-state concentrations are achieved within 24–48 hours with repeated administration. The rate of pregabalin absorption is reduced when administered with food, resulting in approximately a 25–30% decrease in maximum concentration (Cmax) and prolongation of tmax to approximately 2.5 hours. However, co-administration of pregabalin with food does not have a clinically significant effect on the extent of its absorption.

Distribution. Preclinical studies have shown that pregabalin crosses the blood-brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is excreted in the milk of lactating rats. In humans, the volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin does not bind to plasma proteins.

Metabolism. In humans, pregabalin undergoes minimal metabolism. After administration of radiolabeled pregabalin, approximately 98% of the radioactivity was excreted in urine as unchanged pregabalin. The fraction of the N-methylated metabolite of pregabalin — the main metabolite — in urine was 0.9% of the administered dose. Preclinical studies showed no racemization of the S-enantiomer of pregabalin to the R-enantiomer.

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). Dose adjustment is required for patients with renal impairment or patients on hemodialysis (see table in section “Dosage and administration”).

Linearity/non-linearity. The pharmacokinetics of pregabalin are linear over 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 results indicate no clinically significant effect of gender on plasma concentrations of pregabalin.

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

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, 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 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, and 15 mg/kg/day in a pharmacokinetic and tolerability study. After oral administration of pregabalin to children on an empty stomach, the time to reach maximum plasma concentration was generally similar across all age groups, ranging from 0.5 to 2 hours after administration. Cmax and area under the concentration-time curve (AUC) values of pregabalin increased linearly with dose in each age group. In children with body weight 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 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 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 “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 decreases in creatinine clearance. Elderly patients with age-related renal impairment may require dose reduction of pregabalin (see table in section “Dosage and administration”).

Lactation. The pharmacokinetics of pregabalin were evaluated in 10 breastfeeding women who received pregabalin 150 mg every 12 hours (daily dose 300 mg) at least 12 weeks postpartum. Lactation had no or minimal effect on the pharmacokinetics of pregabalin. Pregabalin was excreted in 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) for a woman taking pregabalin at 300 mg/day or the maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the total daily maternal dose normalized to mg/kg.

Clinical Characteristics

Indications

Neuropathic pain. The medicinal product is indicated for the treatment of peripheral or central neuropathic pain in adults.

Epilepsy. The medicinal product is indicated for adults as adjunctive therapy for partial seizures with or without secondary generalization.

Generalized anxiety disorder. The medicinal product is indicated for the treatment of generalized anxiety disorder in adults.

Fibromyalgia.

Contraindications

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

Interaction with other medicinal products and other forms of interaction

Since pregabalin is predominantly excreted unchanged in urine, undergoes 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 this medicinal product would cause or be subject to pharmacokinetic 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 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. During post-marketing surveillance, cases of respiratory depression, coma, and death have been reported in patients who took pregabalin concomitantly with opioids and/or other medicinal products that depress central nervous system (CNS) function. Pregabalin may likely enhance the cognitive and basic motor function impairment caused by oxycodone.

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

Special precautions for use

Patients with diabetes mellitus. According to current clinical practice, some 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 occur, such as facial swelling, perioral swelling, or swelling of the upper airways, pregabalin should be discontinued immediately.

Severe skin reactions. Rare cases of serious skin adverse reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis, have been reported during treatment with pregabalin. These reactions may be life-threatening or fatal. When prescribing pregabalin, patients should be informed about the characteristic signs and symptoms, and skin reactions should be closely monitored. If signs or symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative treatment considered (if necessary).

Dizziness, somnolence, loss of consciousness, confusion, and psychiatric disturbances. Pregabalin use has been associated with dizziness and somnolence, increasing the risk of traumatic events (e.g., falls) in elderly patients. Post-marketing reports have also described cases of loss of consciousness, confusion, and psychiatric disturbances. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of this medicinal product.

Visual disorders. During controlled studies, blurred vision was reported more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this phenomenon 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 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 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. Cases of congestive heart failure have been reported in some patients taking pregabalin following its marketing. This reaction was mostly observed during pregabalin treatment for neuropathic pain in elderly patients with pre-existing cardiovascular disorders. Pregabalin should be used with caution in such patients. This condition may resolve 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 (CNS), such as somnolence, increased. This may be related to the additive effects of concomitant medications (e.g., antispastic agents) required for managing this condition. This should be taken into account when prescribing pregabalin for this indication.

Respiratory depression. Cases of severe respiratory depression have been reported in association with pregabalin use. Patients with impaired respiratory function, respiratory or neurological disorders, renal impairment, those receiving concomitant CNS depressants, and elderly patients may be 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 antiepileptic drug trials also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown. Post-marketing reports have described cases of suicidal ideation 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 within 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 emerge. Patients should be monitored for signs of suicidal thoughts and behavior. If suicidal thoughts or behavior occur, appropriate treatment or discontinuation of pregabalin should be considered.

Worsening of lower gastrointestinal tract function. Post-marketing reports have described events related to worsening of lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) during 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 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 among individuals taking opioids, an increased risk of opioid-related death was observed in patients receiving pregabalin concomitantly with an opioid compared to those receiving opioids alone (adjusted odds ratio [aOR] 1.68 [95% confidence interval (CI) 1.19–2.36]). This increased risk was observed even at low pregabalin doses (≤ 300 mg, aOR 1.52 [95% CI 1.04–2.22]), with a trend toward increased risk at higher pregabalin doses (> 300 mg, aOR 2.55 [95% CI 1.24–5.06]).

Misuse, abuse, or dependence. Pregabalin may cause drug dependence, even at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance abuse are at higher risk of pregabalin misuse, abuse, and dependence, and therefore pregabalin should be used with caution in such patients. Before prescribing pregabalin, the risk of misuse, abuse, or dependence should be carefully assessed. Patients receiving pregabalin should be monitored for signs and symptoms of misuse, abuse, or dependence, such as development of tolerance, dose escalation, and 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 symptoms, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness. The emergence of withdrawal symptoms after stopping pregabalin may indicate drug dependence (see section "Adverse reactions"). This information should be communicated to patients before initiating therapy. If discontinuation of pregabalin is required, it is recommended to taper off gradually over at least 1 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 pregabalin discontinuation 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 concomitant conditions that may predispose to encephalopathy.

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

Lactose intolerance. The medicinal product contains lactose. Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

The medicinal product contains carmoisine (E 122), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Women of childbearing potential / contraceptive methods for women. Women of childbearing potential must use effective contraception during treatment (see section "Special precautions for use").

Pregnancy. Reproductive toxicity has been demonstrated 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. In an observational study conducted in Scandinavian countries, involving over 2700 pregnancies exposed to pregabalin during the first trimester, a higher prevalence of major congenital malformations (MCM) was observed in the population of children (live or stillborn) exposed to pregabalin compared to the unexposed population (5.9% vs. 4.1%). The risk of MCM in children whose mothers took pregabalin during the first trimester of pregnancy 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 malformations, orofacial clefts, urinary tract malformations, and genital organ malformations, although the number of such cases was small and estimates imprecise. The medicinal product should not be used during pregnancy unless clearly necessary (use is permitted only if the expected benefit to the mother clearly outweighs the potential risk to the fetus).

Breastfeeding. 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/day. After 3 months of treatment, no effect on sperm motility was observed. In fertility studies in female rats, adverse effects on reproductive function were observed. In fertility studies 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

The medicinal product may have a minor or moderate influence on the ability to drive and use machines. Pregabalin may cause dizziness and somnolence and thereby affect 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.

Dosage and Administration

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

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

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

Epilepsy. Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the individual patient 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 administrations, may range from 150–600 mg per day. The need for continued therapy should be periodically reassessed. Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on the individual patient response and tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week of dosing, the dose may be increased to 450 mg per day. After an additional week, the dose may be increased to the maximum of 600 mg per day.

Fibromyalgia. The recommended dose of the drug for the treatment of fibromyalgia ranges from 300 to 450 mg per day. Treatment should be initiated 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 evaluated the use of a 600 mg per day dose, there is no evidence that this dose provides additional benefit; furthermore, this dose was associated with poorer tolerability. Considering dose-dependent adverse reactions, doses above 450 mg per day are not recommended. Since the drug is primarily eliminated by the kidneys, dosage adjustment is required in patients with impaired renal function.

Discontinuation of pregabalin. According to current clinical practice, pregabalin therapy should be discontinued gradually over a minimum of one week, regardless of the indication (see sections "Special precautions" 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 reduction in patients with renal impairment should be individualized as indicated in the table below, based on creatinine clearance (CLcr), calculated using the following formula:

Pregabalin is effectively removed from plasma by hemodialysis (50% of the drug within 4 hours). For patients undergoing hemodialydia, 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 procedure (see table).

Adjustment of pregabalin dosage according to renal function.

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

** Administer pregabalin at the appropriate dosage.

• Additional dose — an extra single dose.

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

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

Children

The safety and efficacy of the medicinal product Ligato® in children (under 18 years of age) have not been established. Currently available information is presented in the section "Adverse reactions" and in the sections "Pharmacodynamics" and "Pharmacokinetics"; however, based on this information, no dosage recommendations can be provided for this patient population.

Overdose

Since marketing authorization, the most commonly reported adverse reactions following pregabalin overdose have been somnolence, confusion, agitation, and restlessness. Seizures have also been reported. Coma has been reported rarely. Management of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis (see the table in section "Dosage and administration").

Adverse Reactions

In the clinical development program for pregabalin, more than 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 of mild or moderate severity. In all controlled studies, 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 pregabalin were dizziness and somnolence.

The following is a list of all adverse reactions that occurred more frequently than with placebo and in more than one patient. These adverse reactions are listed 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 grouping, adverse reactions are presented in order of decreasing severity. The listed adverse reactions may also be related to the course of 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"). Adverse reactions additionally 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, difficulty in finding words, abnormal dreams, increased libido, anorgasmia, apathy.
Rare: disinhibition, suicidal ideation, suicidal behavior.
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 disorders, speech disorders, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, apathy, perioral paresthesia, myoclonus.
Rare: convulsions, parosmia, hypokinesia, dysphagia, parkinsonism, hypalgesia, dependence, cerebellar syndrome, cogwheel rigidity, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain–Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders.

Eye disorders.
Common: blurred vision, diplopia, conjunctivitis.
Uncommon: peripheral vision loss, visual disturbance, eye swelling, visual field defects, decreased visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, blepharitis, accommodation disorder, ocular hemorrhage, photophobia, retinal edema.
Rare: vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulceration, exophthalmos, oculomotor 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: prolongation of 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 hemorrhage.
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, 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 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, fatigue.
Uncommon: generalized edema, facial swelling, chest tightness, pain, hot flushes, thirst, chills, general weakness, malaise, abscess, lipodermatitis, photosensitivity reactions.
Rare: granuloma, self-injury, retroperitoneal fibrosis, shock.

Investigations.
Common: weight increased.
Uncommon: increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, weight decreased.
Rare: decreased blood leukocyte count.

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

In some patients, withdrawal symptoms were observed after discontinuation of short-term or long-term pregabalin therapy. Reported reactions included insomnia, headache, nausea, anxiety, diarrhea, influenza-like syndrome, convulsions, restlessness, depression, suicidal thoughts, pain, hyperhidrosis, and dizziness, suggesting physical dependence. This information should be communicated to the patient prior to initiating therapy.

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

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

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

Shelf life. 3 years.

Storage conditions. Store in the original packaging, out of reach of children.

Packaging. 7 capsules in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Medochemie Ltd (Central Factory) / Medochemie LTD (Central Factory).

Manufacturer's address and location of operations.
1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus / 1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.