Linefor capsules 75mg No. 56

Instructions for use Linefor capsules 75mg No. 56

Composition

active ingredient: pregabalin;

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

excipients: lactose monohydrate; corn starch; talc;

capsule shell for 75 mg and 300 mg: gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172);

shell for 150 mg capsules: gelatin, titanium dioxide (E 171);

ink: shellac, black iron oxide (E 172), propylene glycol, ammonium hydroxide.

Dosage form

The capsules are hard.

Main physicochemical properties:

75 mg capsules – hard gelatin capsules with a white body and a red-brown cap with the inscription “75” on the body, capsule size – No. 3;

150 mg capsules – white hard gelatin capsules with the inscription “150” on the body, capsule size – No. 1;

300 mg capsules – hard gelatin capsules with a white body and a red-brown cap with the inscription “300” on the body, capsule size – No. 0.

Pharmacotherapeutic group

Antiepileptic drugs, other antiepileptic drugs.

ATX code N03A X16.

Pharmacological properties

Pharmacodynamics.

The active substance is pregabalin, which is an analogue of gamma-aminobutyric acid ((S)-3-(aminomethylprocesyl)-5-methylhexanoic acid).

Mechanism of action

Pregabalin binds to the auxiliary subunit (a2-d-protein) of voltage-gated calcium channels in the central nervous system (CNS).

Clinical efficacy and safety.

– Neuropathic pain

Pregabalin has been shown to be effective in treating diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. Its effectiveness in other types of neuropathic pain has not been studied.

Pregabalin has been studied in 10 controlled clinical trials of up to 13 weeks duration with twice daily dosing and in trials of up to 8 weeks duration with three times daily dosing. Overall, the safety and efficacy profiles were similar for the two- and three-times-daily dosing regimens.

In clinical studies lasting up to 12 weeks in which the drug was used to treat neuropathic pain, a reduction in peripheral and central pain was observed after the first week and was maintained throughout the treatment period.

In controlled clinical trials of peripheral neuropathic pain, 35% of patients treated with pregabalin and 18% of patients treated with placebo achieved a 50% improvement in pain scores. Among patients who did not experience somnolence, this improvement was observed in 33% of patients treated with pregabalin and 18% of patients treated with placebo. Among patients who experienced somnolence, the proportion of patients who responded to treatment was 48% in the pregabalin group and 16% in the placebo group.

In a controlled clinical trial in central neuropathic pain, 22% of patients treated with pregabalin and 7% of patients treated with placebo had a 50% improvement in pain scores.

– Epilepsy

Add-on therapy: Pregabalin has been 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 the twice-daily and three-times-daily dosing regimens were similar.

A decrease in the frequency of seizures was observed already in the first week.

Children.

The efficacy and safety of pregabalin as an 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 in patients aged 3 months to 16 years (n=65) with partial onset seizures were similar to those seen in adults. Results from a 12-week placebo-controlled study in 295 children aged 4 to 16 years, a 14-day study in 175 children aged 1 month to 4 years to evaluate the efficacy and safety of pregabalin as adjunctive therapy in partial onset seizures, and two 1-year open-label safety studies in 54 and 431 children aged 3 months to 16 years with epilepsy indicate that adverse reactions such as pyrexia and upper respiratory tract infections are more common in children than in adult patients with epilepsy (see sections 5.2, 5.2 and 4.8).

In a 14-day placebo-controlled study, children (aged 1 month to 4 years) were treated with pregabalin 7 mg/kg/day, pregabalin 14 mg/kg/day, or placebo. The median seizure frequency at baseline and at the end of the study was 4.7 and 3.8, respectively, for pregabalin 7 mg/kg/day, 5.4 and 1.4, respectively, for pregabalin 14 mg/kg/day, and 2.9 and 2.3, respectively, for placebo. Pregabalin 14 mg/kg/day significantly reduced the log-transformed incidence of partial-onset seizures compared with placebo (p=0.023); however, pregabalin 7 mg/kg/day showed no improvement compared with placebo.

Monotherapy (in newly diagnosed patients). Pregabalin was studied in 1 controlled clinical trial of 56 weeks duration with a twice daily dosing regimen. Pregabalin was non-inferior to lamotrigine as assessed at 6 months for the seizure-free endpoint. Pregabalin and lamotrigine were equally safe and well tolerated.

– Generalized anxiety disorder

Pregabalin has been studied in 6 controlled trials of 4–6 weeks duration, one 8-week study in elderly patients, and one long-term relapse prevention trial with a double-blind relapse prevention phase of 6 months duration.

A reduction in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Assessment Scale (HAM-A) was observed as early as week 1.

In controlled clinical trials (4–8 weeks duration), 52% of patients treated with pregabalin and 38% of patients treated with placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.

In controlled trials, blurred vision was more frequently observed in patients treated with pregabalin than in patients treated with placebo. In most cases, this phenomenon resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and dilated fundus examination) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity deteriorated in 6.5% of patients in the pregabalin group and 4.8% of patients in the placebo group. Visual field changes were observed in 12.4% of patients treated with pregabalin and 11.7% of patients in the placebo group. Fundus changes were observed in 1.7% of patients treated with 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 study (F1) and one 6-week, randomized withdrawal study (F2). These studies enrolled patients diagnosed with fibromyalgia based on the American College of Rheumatology criteria (3-month history of widespread pain and pain present in 11 or more of 18 specific tender points). The studies demonstrated a reduction in pain on a visual analog scale. Improvement was additionally demonstrated on the patient's global assessment and on a fibromyalgia impact questionnaire.

Children: A 15-week placebo-controlled study was conducted in 107 children aged 12-17 years with fibromyalgia who received pregabalin at a dose of 75-450 mg/day. The primary efficacy endpoint (change in total pain intensity from baseline to week 15; calculated using an 11-point rating scale) demonstrated a numerically greater improvement in patients treated with pregabalin compared to patients treated with placebo, but this improvement did not reach statistical significance. The most common adverse reactions observed in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics.

The pharmacokinetics of pregabalin are similar in healthy volunteers, patients with epilepsy taking antiepileptic drugs, and patients with chronic pain.

Absorption: Pregabalin is rapidly absorbed after oral administration in the fasted state and reaches peak plasma concentrations (Cmax) within 1 hour after single and multiple doses. The estimated oral bioavailability of pregabalin is greater than 90% and is independent of dose. Steady state is reached within 24–48 hours after repeated administration. The extent of pregabalin absorption is reduced when administered with food, resulting in a decrease in Cmax of approximately 25–30% and a delay in time to peak concentration (tmax) of approximately 2.5 hours. However, administration of pregabalin with food had no clinically significant effect on the extent of absorption.

Metabolism: Pregabalin undergoes minimal metabolism in humans. Following an administered dose of radiolabeled pregabalin, approximately 98% of the radioactivity is excreted in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin (the major metabolite of pregabalin detected in urine) accounted for 0.9% of the administered dose.

Elimination: Pregabalin is eliminated from the systemic circulation primarily by renal excretion of unchanged pregabalin. The mean elimination half-life of pregabalin is 6.3 hours. The plasma and renal clearance of pregabalin are directly proportional to creatinine clearance. Dosage adjustment is required in patients with renal impairment or undergoing hemodialysis.

Linearity/non-linearity. The pharmacokinetics of pregabalin are linear over the recommended dosing range. The intersubject pharmacokinetic variability for pregabalin is low (less than 20%). Multiple-dose pharmacokinetics are predictable from single-dose data. Therefore, there is no need for routine monitoring of pregabalin plasma concentrations.

Pharmacokinetics in specific patient groups

Gender: There is no clinically significant effect of gender on pregabalin plasma concentrations.

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, the plasma concentration of pregabalin is reduced by approximately 50%). Since renal excretion is the primary route of drug elimination, patients with renal impairment should have their dose reduced and an additional dose administered after hemodialysis.

Hepatic impairment: No specific pharmacokinetic studies have been conducted in patients with hepatic impairment. Since pregabalin is not significantly metabolized and is excreted primarily unchanged in the urine, hepatic impairment is unlikely to affect pregabalin plasma concentrations.

Children: The pharmacokinetics of pregabalin were evaluated in children with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years, and 12 to 16 years) at doses of 2.5 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 in the fasted state, the time to peak plasma concentration was generally similar across age groups and ranged from 0.5 to 2 hours post-dose. Pregabalin Cmax and AUC increased linearly with increasing dose in each age group. In children weighing <30 kg, AUC values were 30% lower, due to a 43% increase in weight-adjusted clearance in these patients compared to patients weighing ≥30 kg.

The terminal half-life of pregabalin averaged approximately 3–4 hours in children under 6 years of age and 4–6 hours in children over 7 years of age.

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

The pharmacokinetics of pregabalin in patients under 3 months of age have not been studied (see sections 5.1, 5.2, and 4.8).

Elderly patients (over 65 years of age). Pregabalin clearance tends to decrease with age. This decrease in oral pregabalin clearance is consistent with the age-related decrease in creatinine clearance. Patients with age-related renal impairment may require a reduction in the dose of pregabalin.

Breastfeeding. The pharmacokinetics of pregabalin, administered at a dose of 150 mg every 12 hours (300 mg daily dose), were evaluated in 10 lactating women for at least 12 weeks postpartum. Breastfeeding had no or negligible effect on the pharmacokinetics of pregabalin. Pregabalin was excreted in breast milk, with mean steady-state concentrations approximately 76% of maternal plasma concentrations. The estimated dose to the breastfed infant (with a mean milk intake of 150 ml/kg/day) from a woman taking pregabalin at a dose of 300 mg/day or a maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These estimated doses represent approximately 7% of the total maternal daily dose on a mg/kg basis.

Indication

Neuropathic pain.

Treatment of neuropathic pain of peripheral or central origin in adults.

Epilepsy.

Adjunctive treatment of partial seizures with or without secondary generalization in adults.

Generalized anxiety disorder.

Treatment of generalized anxiety disorder in adults.

Fibromyalgia.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the drug.

Interaction with other medicinal products and other types of interactions

Since pregabalin is mainly excreted unchanged in the urine, undergoes little metabolism in humans (less than 2% of the dose is excreted in the 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 can cause or be the target of pharmacokinetic drug interactions.

In vivo studies and population pharmacokinetic analysis

Accordingly, no clinically relevant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol in in vivo studies. Population pharmacokinetic analysis showed that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine and topiramate had no clinically relevant effect on pregabalin clearance.

Oral contraceptives, norethisterone and/or ethinyl estradiol

Co-administration of pregabalin and the oral contraceptives, norethisterone and/or ethinyl estradiol, does not affect the steady-state pharmacokinetics of either drug.

Drugs that affect the CNS

Pregabalin may potentiate the effects of ethanol and lorazepam. Multiple oral doses of pregabalin and oxycodone, lorazepam, or ethanol are known to have no clinically significant effects on respiratory function.

In the post-marketing period, respiratory failure, coma and fatalities have been reported in patients taking pregabalin concomitantly with opioids and/or other CNS depressants, particularly in patients with a history of substance abuse. Pregabalin potentiated the cognitive and motor impairments caused by oxycodone.

Interactions in elderly patients

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

Application features

Patients with diabetes

In accordance with current clinical practice, some patients with diabetes mellitus who gain weight during treatment with pregabalin may require dose adjustment of hypoglycemic drugs.

Hypersensitivity reactions

Hypersensitivity reactions, including angioedema, have been reported. If symptoms of angioedema such as facial, perioral or upper respiratory tract swelling occur, pregabalin should be discontinued immediately.

Dizziness, drowsiness, loss of consciousness, confusion and mental disorders

Pregabalin has been associated with dizziness and somnolence, which may increase the risk of accidental injury (fall) in the elderly. Loss of consciousness, confusion, and mental impairment have been reported in the post-marketing setting. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of the drug.

Vision disorders

In controlled trials, a greater proportion of patients treated with pregabalin experienced blurred vision compared with patients treated with placebo. These effects resolved in most cases with continued treatment. In clinical trials in which ophthalmological examinations were performed, the incidence of decreased visual acuity and visual field changes was higher in patients treated with pregabalin than in patients treated with placebo; the incidence of fundus changes was higher in patients treated with placebo.

In the post-marketing period, visual side effects including vision loss, blurred vision or other changes in visual acuity have been reported, most of which were transient. Discontinuation of pregabalin may resolve or reduce these symptoms.

Kidney failure

Cases of renal failure have been reported. This effect was sometimes reversible after discontinuation of pregabalin.

Withdrawal of concomitant antiepileptic drugs

There are insufficient data on the withdrawal of concomitant antiepileptic drugs after seizure control is achieved when pregabalin is added to existing treatment to switch to pregabalin monotherapy.

Withdrawal symptoms

Withdrawal symptoms have been observed in some patients after discontinuation of short-term and long-term use of pregabalin. The following events have been reported: insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, nervousness, depression, pain, seizures, hyperhidrosis, and dizziness, which are indicative of physical dependence. This information should be communicated to the patient before starting treatment.

Convulsions, including status epilepticus and grand mal seizures, may occur during treatment with pregabalin or shortly after discontinuation of its use.

Regarding discontinuation of long-term pregabalin treatment, data suggest that the incidence and severity of withdrawal symptoms may be dose-dependent.

Although a causal relationship between pregabalin and congestive heart failure has not been established, cases of congestive heart failure have been reported in patients treated with pregabalin in the post-marketing setting. This reaction has occurred predominantly in patients treated with pregabalin for neuropathic pain in elderly patients with pre-existing cardiovascular disease. As there is limited data in patients with severe congestive heart failure, pregabalin should be used with caution in such patients. This phenomenon may resolve upon discontinuation of pregabalin.

Treatment of neuropathic pain of central origin due to spinal cord injury

In the treatment of central neuropathic pain due to spinal cord injury, the incidence of adverse reactions in general, CNS adverse reactions and somnolence in particular was increased. This may be explained by the additive effect of other medicinal products (e.g. antispasticity agents) required for the treatment of this condition. This should be taken into account when prescribing pregabalin to such patients.

Suicidal thinking and behavior

Suicidal ideation and behavior have been observed in patients treated with antiepileptic drugs for certain indications. There is a slightly increased risk of suicidal ideation and behavior with antiepileptic drugs. The mechanism of this risk is unknown, and the available data do not exclude it for patients taking pregabalin.

Therefore, patients should be monitored closely for signs of suicidal ideation and behavior and treated appropriately if they emerge. Patients (and their caregivers) should seek medical advice if suicidal ideation and behavior emerge.

Lower gastrointestinal dysfunction

Lower gastrointestinal events (such as intestinal obstruction, paralytic ileus, constipation) have been reported following the concomitant use of pregabalin with medicinal products that may cause constipation, such as opioid analgesics. Precautions should be taken to prevent constipation when pregabalin is used concomitantly with opioids (especially in women and the elderly).

Misuse, addictive potential or dependence

Cases of misuse, abuse and dependence have been reported. The drug should be prescribed with caution to patients with a history of substance abuse, and these patients require close medical supervision for misuse, abuse or the development of symptoms of dependence on pregabalin (cases of tolerance, dose escalation and drug-seeking behavior have been reported).

Encephalopathy

Cases of encephalopathy occurred predominantly in patients with concomitant diseases that could cause encephalopathy.

Respiratory depression

Severe respiratory depression has been reported in association with pregabalin treatment. Patients with respiratory impairment, respiratory or central nervous system disease, renal disease, or those taking other CNS depressant medications, or elderly patients may be at higher risk of developing this severe adverse reaction. Dose adjustment may be necessary in these patients.

Concomitant use with opioids

Caution is advised when prescribing pregabalin concomitantly with opioids due to the risk of CNS depression (see section 4.5). In a case-control study of opioid users, those patients receiving pregabalin concomitantly with an opioid had an increased risk of opioid-related mortality compared with opioids alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19–2.36]). This increased risk was observed at low doses of pregabalin (≤ 300 mg, 1.52 aOR [95% CI, 1.04–2.22]), and there was a trend toward increased risk at high doses of pregabalin (> 300 mg, 2.55 aOR [95% CI, 1.24–5.06]).

The medicine contains propylene glycol, which may cause symptoms similar to those that occur when drinking alcohol.

Linefor contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The 75 mg capsule contains 27 mg of lactose.

The 150 mg capsule contains 54 mg of lactose.

The 300 mg capsule contains 108 mg of lactose.

Use during pregnancy or breastfeeding

Women of reproductive age/contraception for women and men

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

Pregnancy

There are no reliable data on the use of pregabalin in pregnant women.

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

Pregabalin should not be used during pregnancy, except in exceptional cases where the benefit to the pregnant woman clearly outweighs the potential risk to the fetus.

Pregabalin is excreted in human milk. The effect of pregabalin on newborns/infants is unknown. Therefore, breast-feeding is not recommended during treatment with pregabalin.

Fertility

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

After 3 months of pregabalin treatment, no effect on sperm motility was detected.

A fertility study showed adverse effects on female reproductive function in rats and adverse effects on male reproductive function and development in rats. The clinical relevance of these findings is unknown.

Ability to influence reaction speed when driving vehicles or other mechanisms

Pregabalin may have minor or moderate influence on the ability to drive and use machines. Pregabalin may cause dizziness and drowsiness and may affect the ability to drive or use machines. Therefore, patients should be advised to refrain from driving or operating complex machinery until it is known how the drug affects the reaction speed.

Method of administration and doses.

Method of application.

The drug Linefor is taken regardless of food intake.

This medicine is for oral use only.

Doses.

The dosage range of the drug can vary between 150–600 mg per day. The daily dose is divided into 2 or 3 doses.

Neuropathic pain

Pregabalin therapy can be initiated at a dose of 150 mg/day, divided into 2 or 3 doses. Depending on the individual response and tolerability of the drug by the patient, the dose can be increased to 300 mg/day after 3–7 days, and if necessary, to a maximum dose of 600 mg/day after another 7 days.

Epilepsy

Pregabalin therapy can 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 drug by the patient, the dose can be increased to 300 mg per day after the first week of treatment. After another week, the dose can be increased to a maximum of 600 mg per day.

Generalized anxiety disorder

The dose, divided into 2 or 3 doses, may vary between 150 and 600 mg per day. The need for continued therapy should be reviewed periodically.

Pregabalin therapy can be initiated at a dose of 150 mg per day. Depending on the individual response and tolerability of the drug by the patient, the dose can be increased to 300 mg per day after the first week of treatment. After another week of treatment, the dose can be increased to 450 mg per day. After another week, the dose can be increased to a maximum of 600 mg per day.

Fibromyalgia

The recommended dose for the treatment of fibromyalgia is 300-450 mg per day. Treatment should be initiated at 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 for whom 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 been conducted with a dose of 600 mg per day, there is no evidence that this dose would provide additional benefit; it was also less well tolerated. Given the dose-related adverse reactions, doses above 450 mg per day are not recommended. Since the drug is excreted primarily by the kidneys, the dose should be adjusted in patients with impaired renal function.

Pregabalin withdrawal

In accordance with current clinical practice, it is recommended to discontinue pregabalin therapy gradually, over a period of at least one week, regardless of the indication (see sections “Special warnings and precautions for use” and “Adverse reactions”).

Kidney dysfunction

Pregabalin is eliminated from the systemic circulation unchanged, primarily by the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section 5.2), the dose should be reduced in patients with renal impairment on an individual basis as indicated in the table below, based on creatinine clearance (CLcr), which is determined by the formula:

Pregabalin is effectively removed from plasma by haemodialysis (50% of the drug within 4 hours). For patients on haemodialysis, 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 haemodialysis session (see table).

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

+ An additional dose is an additional single dose.

No dose adjustment is necessary for patients with hepatic impairment (see Pharmacokinetics).

Elderly patients

Elderly patients may require a reduction in the dose of pregabalin due to decreased renal function (see section 4.4).

Children.

The safety and efficacy of pregabalin in children (under 18 years of age) have not been established. Currently available information is provided in the section "Adverse reactions", as well as in the sections "Pharmacodynamics" and "Pharmacokinetics", however, based on this information, no dosage recommendations can be made for this category of patients.

Overdose

Post-marketing reports have shown that the most frequently reported adverse reactions in cases of pregabalin overdose were drowsiness, confusion, agitation and restlessness. Convulsions have also been reported.

Coma has been reported occasionally.

Treatment of pregabalin overdose consists of general supportive measures and may include hemodialysis if necessary (see section “Method of administration and dosage”, table).

Adverse reactions

In the clinical program for pregabalin, more than 8,900 patients received it, of whom 5,600 were participants in double-blind, placebo-controlled studies. The most frequently reported adverse reactions were dizziness and somnolence. Adverse reactions were usually 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 patients taking placebo. The most common adverse reactions leading to discontinuation of study drug in the pregabalin group were dizziness and somnolence.

All adverse reactions that occurred more frequently than placebo and in more than one patient are listed below; these adverse reactions are listed by system organ class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency unknown (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

During the treatment of central neuropathic pain due to spinal cord injury, the incidence of adverse reactions in general, CNS adverse reactions and especially drowsiness was increased.

The adverse reactions listed below may be related to the underlying disease and/or concomitant use of other medications.

Additional adverse reactions reported during post-marketing experience are indicated in italics in the list below.

Infections and infestations: common: nasopharyngitis.

Immune system disorders: infrequently - hypersensitivity; rarely - angioedema, allergic reactions, anaphylactoid reactions.

Blood and lymphatic system disorders: uncommon - neutropenia.

Metabolism and nutrition disorders: often - increased appetite; infrequently - anorexia, hypoglycemia.

On the part of the psyche: often - euphoric mood, confusion, irritability, disorientation, insomnia, decreased libido; infrequently - hallucinations, panic attacks, anxiety, agitation, depression, depressed mood, elevated mood, aggression, mood swings, depersonalization, difficulty finding words, abnormal dreams, increased libido, anorgasmia, apathy; rarely - disinhibition.

Nervous system disorders: very common: dizziness, drowsiness, headache; common: ataxia, coordination disorder, tremor, dysarthria, amnesia, memory impairment, disturbance in attention, paresthesia, hypoesthesia, sedation, balance disorder, lethargy; uncommon: syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural memory loss