Pregalika

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

Composition:

Active substance: pregabalin;

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

Excipients: pregelatinized starch, mannite (E 421), talc.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

• 75 mg capsules: white powder in a hard gelatin capsule with a white body and red-orange cap, imprinted with "75" on the body;
• 150 mg capsules: white powder in a hard gelatin capsule with a white body and white cap, imprinted with "150" on the body;
• 300 mg capsules: white powder in a hard gelatin capsule with a white body and red-orange cap, imprinted with "300" on the body.

Pharmacotherapeutic group. Antiepileptic agents. Other antiepileptic agents. ATC code N03AX16.

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 for 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 dosing 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 peripheral and central pain was observed after the first week and persisted throughout the entire 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 patients in the placebo group. Among patients who experienced somnolence, the proportion of responders was 48% in the pregabalin group and 16% in the placebo group.

In a controlled clinical trial 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 of 12 weeks' duration with a dosing regimen of twice or three times daily. 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 in 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 study involving 295 children aged 4 to 16 years, designed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and from a 1-year open-label safety study involving 54 children aged 3 months to 16 years with epilepsy indicate that adverse reactions such as pyrexia and upper respiratory tract infections occur more frequently in children than in adult patients with epilepsy (see sections "Dosage and administration", "Adverse reactions", and "Pharmacokinetics"). In the 12-week placebo-controlled study, children 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 from 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 those receiving placebo.

Monotherapy (in patients with newly diagnosed disease). Pregabalin was studied in one controlled clinical trial of 56 weeks' duration with a twice-daily dosing regimen. When pregabalin was used, it did not achieve the same level of efficacy as lamotrigine, as assessed at 6 months using the primary endpoint of seizure freedom. Pregabalin and lamotrigine were equally safe and well tolerated.

• Generalized anxiety disorder.

Pregabalin was studied in six controlled trials of 4–6 weeks' duration, one 8-week trial involving elderly patients, and one long-term relapse prevention trial with a double-blind relapse prevention phase lasting 6 months.

Reduction in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Rating Scale (HAM-A) was observed as early as week 1. In controlled clinical trials (4–8 weeks' duration), improvement of at least 50% in the total HAM-A score from baseline to endpoint was observed in 52% of patients receiving pregabalin and in 38% of patients in the placebo group.

During controlled trials, blurred vision occurred more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this effect resolved with continued therapy. Ophthalmologic examinations (including visual acuity testing, formal visual field testing, and fundoscopic 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. Fundoscopic changes were observed in 1.7% of patients receiving pregabalin and in 2.1% of patients in the placebo group.

• Fibromyalgia.

The efficacy of pregabalin was established in one 14-week double-blind placebo-controlled multicenter trial (F1) and one 6-week randomized withdrawal trial (F2). These trials included patients diagnosed with fibromyalgia based on American College of Rheumatology criteria (widespread pain for at least 3 months and pain 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 fibromyalgia impact questionnaire.

Children. A 15-week placebo-controlled trial was conducted in 107 children aged 12–17 years with fibromyalgia who received pregabalin at doses of 75–450 mg/day. Based on the assessment of 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 after fasting administration 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. At steady state, equilibrium is achieved within 24–48 hours. The rate of pregabalin absorption 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 did 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. It has been established that pregabalin crosses the placenta in rats and is excreted into the milk of lactating rats. In humans, the volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin does not bind to plasma proteins.

Metabolism.

In humans, pregabalin undergoes minimal metabolism. After administration of a radiolabeled dose of pregabalin, approximately 98% of the radioactivity was excreted in urine as unchanged pregabalin. The fraction of the N-methylated metabolite of pregabalin – the main metabolite of the drug detected in urine – accounted for 0.9% of the administered dose. During preclinical studies, no racemization of the S-enantiomer of pregabalin to the R-enantiomer occurred.

Elimination.

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

Dose adjustment of the medicinal product is required in patients with renal impairment or in 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 obtained from single-dose administration. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.

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 in patients with renal impairment, and a supplemental dose should be administered 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 in urine predominantly unchanged, it is unlikely that hepatic impairment would have a significant effect on plasma concentrations of pregabalin.

Children.

The pharmacokinetics of pregabalin were evaluated in children with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years, and 12 to 16 years) receiving doses of 2.5 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, and 15 mg/kg/day in a pharmacokinetic and tolerability study.

After oral administration of pregabalin to children 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 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-adjusted clearance in these patients compared to patients with body weight ≥30 kg. The terminal elimination half-life of pregabalin averaged approximately 3–4 hours in children under 6 years of age and 4–6 hours in children aged 7 years and older.

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

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 decrease in pregabalin clearance with oral administration is consistent with the age-related decrease in creatinine clearance. Elderly patients with renal impairment related to age may require dose reduction of pregabalin (see section "Dosage and administration", Table 1).

Lactation.

The pharmacokinetics of pregabalin were evaluated in 10 breastfeeding women receiving a dose of 150 mg every 12 hours (daily dose 300 mg), at least 12 weeks postpartum. Breastfeeding did not affect or had a negligible effect on the pharmacokinetics of pregabalin. Pregabalin passed into breast milk, with average steady-state concentrations of 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 a dose of 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.

Treatment of peripheral or central neuropathic pain in adults.

Epilepsy.

As adjunctive therapy for partial seizures with or without secondary generalization.

Generalized anxiety disorder.

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

In vivo studies and population pharmacokinetic analysis.

Thus, 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/or ethinylestradiol.

Concomitant administration of pregabalin with oral contraceptives, norethisterone, and/or ethinylestradiol does not affect the steady-state pharmacokinetics of any of these medicinal products.

Medicinal products affecting the CNS.

Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, repeated multiple oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in clinically significant effects on respiratory function. However, there are case reports of respiratory depression, coma, and fatal outcomes in patients who took pregabalin together with opioids and other centrally acting depressant drugs, particularly in patients who abused these substances. Pregabalin is likely to enhance cognitive and gross motor function impairment caused by oxycodone.

Interactions in elderly patients.

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

Special precautions for use.

Patients with diabetes mellitus.

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

Hypersensitivity reactions.

There are documented cases of hypersensitivity reactions, including angioedema, associated with pregabalin use. If symptoms of angioedema such as facial swelling, perioral swelling, or swelling of the upper airways occur, pregabalin must be discontinued immediately.

Severe skin reactions.

Rare cases of severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with pregabalin treatment, which may be life-threatening or fatal.

Patients should be informed about the signs and symptoms of such reactions, and skin reactions should be closely monitored during treatment. If signs or symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative therapy considered (if necessary).

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

Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of traumatic events (falls) in elderly patients. Cases of loss of consciousness, confusion, and psychiatric disturbances have been reported with pregabalin use. 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 observed more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this phenomenon resolved with continued therapy. In clinical trials involving ophthalmological examinations, the incidence of decreased visual acuity and visual field changes was higher in patients receiving pregabalin compared to placebo; however, the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacodynamics").

There are documented ocular adverse reactions associated with pregabalin use, 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 by adding pregabalin to the treatment regimen, in order to switch to pregabalin monotherapy.

Withdrawal symptoms.

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

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

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

Heart failure.

There are documented cases of congestive heart failure in some patients receiving pregabalin. This reaction was mostly observed during pregabalin treatment of neuropathic pain in elderly patients with pre-existing cardiovascular disorders. Pregabalin should be used with caution in such patients. This phenomenon may resolve upon discontinuation of pregabalin.

Treatment of central neuropathic pain due to spinal cord injury.

During treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly those affecting the central nervous system and especially 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, concomitant use of CNS depressants, and elderly patients may be at higher risk of this serious adverse reaction. Dose adjustment may be required in these patients.

Suicidal thoughts and behavior.

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

Therefore, patients should be closely monitored for signs of suicidal thoughts and behavior, and appropriate treatment should be considered. If signs of suicidal thoughts or behavior emerge, patients (and their caregivers) should seek immediate medical help. In cases of suicidal thoughts or behavior, discontinuation of pregabalin therapy should be considered.

Worsening of lower gastrointestinal tract function.

There are documented cases of worsening lower gastrointestinal tract function (such as intestinal obstruction, paralytic ileus, constipation) associated with pregabalin use, particularly when used concomitantly 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.

Pregabalin should be prescribed with caution when used concomitantly with opioids due to the risk of CNS depression. In a controlled study of opioid users, patients receiving pregabalin concomitantly with an opioid had an increased risk of opioid-related death compared to those receiving opioids alone. This increased risk was observed at low pregabalin doses (≤ 300 mg, aOR 1.52 [95% CI, 1.04–2.22]), with a trend toward greater risk at higher pregabalin doses (> 300 mg, aOR 2.51 [95% CI 1.24–5.06]).

Improper use, abuse, or dependence.

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

Encephalopathy.

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

Excipients.

The medicinal product Prigalika contains mannitol, which may have a mild laxative effect.

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception for women and men.

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

Pregnancy.

Adequate data on pregabalin use in pregnant women are lacking.

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

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

Breastfeeding.

Pregabalin is excreted in breast milk. The effect of pregabalin on newborns/infants is unknown. A decision must be made whether to discontinue breastfeeding or to discontinue pregabalin therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

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.

Ability to affect reaction speed when driving vehicles or operating machinery.

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

Dosage and Administration

The medicinal product Pregalika should be taken independently of food intake. The medicinal product is intended exclusively for oral administration.

Doses.

The dose 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.

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

Epilepsy.

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the individual response and tolerability of the medicinal product by the patient, 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 between 150–600 mg per day. The necessity of continuing therapy should be periodically reviewed.

Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on the individual response and tolerability of the medicinal product by the patient, 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 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 has evaluated the use of a 600 mg daily dose, there is no evidence that this dose provides additional benefit; furthermore, this dose was associated with poorer tolerability. Given the dose-dependent adverse reactions, doses exceeding 450 mg per day are not recommended. Since Pregalika 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 Warnings" and "Adverse Reactions").

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"), the dose should be individually reduced in patients with renal impairment, as indicated in the table below, according to 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 additional dose of the medicinal product should be administered immediately after each 4-hour hemodialysis procedure (see table).

Dose adjustment of pregabalin according to renal function.

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

• Additional dose means an extra single dose.

Hepatic impairment.

Dose adjustment is not required for patients with impaired liver function (see section "Pharmacokinetics").

Elderly patients.

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

Children.

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

Overdose.

Symptoms. The most commonly reported adverse reactions in pregabalin overdose have been somnolence, confusion, agitation and restlessness. Seizures have also been reported. Coma has been reported rarely.

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

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 usually 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 the study drug in the pregabalin group were dizziness and somnolence.

Below are all adverse reactions that occurred more frequently than with placebo and in more than one patient. These adverse reactions are listed by system organ classes and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated based on available data). Within each frequency grouping, adverse effects are presented in order of decreasing severity.

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

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

Additional adverse reactions reported during the post-marketing surveillance period 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 swings, depersonalization, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition, parkinsonism, suicidal behaviour, suicidal ideation.

Nervous system disorders.

Very common: dizziness, somnolence, headache.

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

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

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

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 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, arterial hypertension, flushing, hyperemia, cold sensation in extremities.

Respiratory, thoracic and mediastinal disorders.

Common: pharyngolaryngeal pain.

Uncommon: dyspnea, epistaxis, cough, nasal congestion, rhinitis, snoring, dryness of nasal mucosa.

Rare: pulmonary edema, throat tightness, laryngospasm, apnea, atelectasis, bronchiolitis, hiccups, pulmonary fibrosis, yawning.

Gastrointestinal disorders.

Common: vomiting, nausea, constipation, diarrhea, flatulence, abdominal distension, dry mouth, gastroenteritis.

Uncommon: gastroesophageal reflux disease, hypersalivation, oral hypoaesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, tongue swelling, rectal bleeding.

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

Hepatobiliary disorders.

Uncommon: increased liver enzymes*.

Rare: jaundice.

Very rare: hepatic failure, hepatitis.

Skin and subcutaneous tissue disorders.

Common: pressure ulcers.

Uncommon: papular rash, urticaria, hyperhidrosis, pruritus, alopecia, dry skin, eczema, hirsutism, skin ulcers, vesiculobullous rash.

Rare: Stevens-Johnson syndrome, cold sweat, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail disorders, petechial rash, purpura, pustular rash, skin atrophy, skin necrosis, skin and subcutaneous nodules, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders.

Common: muscle cramps, arthralgia, back pain, limb pain, neck muscle spasms.

Uncommon: joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness.

Rare: rhabdomyolysis.

Renal and urinary disorders.

Uncommon: urinary incontinence, dysuria, albuminuria, hematuria, kidney stone formation, nephritis.

Rare: renal failure, oliguria, urinary retention, acute renal failure, glomerulonephritis, pyelonephritis.

Reproductive system and breast disorders.

Common: erectile dysfunction, impotence.

Uncommon: sexual dysfunction, ejaculation 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, generalized 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, seizures, restlessness, depression, 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. Pediatric population. The safety profile of pregabalin established in three studies involving pediatric patients with partial seizures with or without secondary generalization (a 12-week efficacy and safety study in patients with partial seizures, n=295; a pharmacokinetic and tolerability study, n=65; and a 1-year open-label safety study, n=54) was similar to that observed in adult epilepsy studies. The most commonly reported adverse events in the 12-week pregabalin treatment study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis (see sections "Dosage and administration", "Pharmacodynamics", and "Pharmacokinetics").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store below 25 °C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging.

10 capsules in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

FARMATEN INTERNATIONAL SA

Manufacturer's address and location of operations.

Industrial Park Sapes Prefecture Rodopi, Block No. 5, Rodopi, 69300, Greece.