Pregabalin-Darnitsa capsules 150 mg No. 21

Instructions for use Pregabalin-Darnitsa capsules 150 mg No. 21

Composition

active ingredient: pregabalin;

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

excipients: lactose monohydrate, corn starch, talc;
hard gelatin capsules: gelatin, titanium dioxide (E 171).

Dosage form

Capsules.

Main physicochemical properties: hard gelatin capsules with a white or almost white cap and body, containing a white or almost white powder.

Pharmacotherapeutic group

Antiepileptics. Other antiepileptics. Pregabalin. ATX code N03A X16.

Pharmacological properties

Pharmacodynamics.

The active substance is pregabalin, which is an analogue of gamma-aminobutyric acid [(S)-3-(aminomethyl)-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. Pregabalin has not been studied for other types of neuropathic pain.

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

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 and in 18% of patients in the placebo group. Among patients who experienced somnolence, the proportion of patients who responded to therapy was 48% in the pregabalin group and 16% in the placebo group.

In a controlled clinical trial of 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 observed in adults. Results from a 12-week placebo-controlled study in 295 children aged 4 to 16 years and
A 14-day placebo-controlled study in 175 children aged 1 month to 4 years to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial onset seizures, and two 1-year open-label safety studies in 54 and 431 children aged 3 months to 16 years with epilepsy, respectively, 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 12-week placebo-controlled study, children (aged 4 to 16 years) were given pregabalin 2.5 mg/kg/day (maximum 150 mg/day), pregabalin 10 mg/kg/day (maximum 600 mg/day), or placebo. The percentage of patients with a reduction in partial onset seizures, at least a 50% reduction in partial onset seizures from baseline, was observed in 40.6% of patients receiving pregabalin 10 mg/kg/day (p=0.0068 vs. placebo), 29.1% of patients receiving pregabalin 2.5 mg/kg/day (p=0.2600 vs. placebo), and 22.6% of those receiving placebo.

In a 12-week placebo-controlled study, 219 patients with primary generalized tonic-clonic seizures (aged 5 to 65 years, of whom 66 were aged 5 to 16 years) were treated with pregabalin 5 mg/kg/day (maximum 300 mg/day), 10 mg/kg/day (maximum 600 mg/day), or placebo as adjunctive therapy. The percentage of patients with at least a 50% reduction in primary generalized tonic-clonic seizure frequency was 41.3%, 38.9%, and 41.7% for pregabalin 5 mg/kg/day, pregabalin 10 mg/kg/day, and placebo, respectively.

Monotherapy (in patients with newly diagnosed disease)

Pregabalin was studied in 1 controlled clinical trial of 56 weeks duration with a twice daily dosing regimen. Pregabalin did not achieve the same level of efficacy compared to lamotrigine as assessed by the 6-month 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 the first week.

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 to 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 with 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 steady-state pharmacokinetics of pregabalin were similar in healthy volunteers, patients with epilepsy taking antiepileptic drugs, and patients with chronic pain.

Absorption

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

Distribution

In preclinical studies, pregabalin has been shown to cross the blood-brain barrier in mice, rats, and monkeys. In rats, pregabalin has been shown to cross the placenta and to be secreted into milk during lactation. In humans, the volume of distribution of pregabalin after oral administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins.

Pregabalin undergoes minimal metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 98% of the radioactivity was 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. In nonclinical studies, there was no racemization of the S-enantiomer of pregabalin to the R-enantiomer.

Breeding

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

Patients with impaired renal function or patients on hemodialysis require dose adjustment of the drug (see section "Method of administration and dosage", table).

Linearity/nonlinearity

The pharmacokinetics of pregabalin are linear over the recommended dose range. The interpatient variability in the pharmacokinetics of pregabalin is low (< 20%). The pharmacokinetics of multiple doses are predictable from single-dose data. Therefore, routine monitoring of pregabalin plasma concentrations is not required.

Sex

Results of clinical studies indicate that there is no clinically significant effect of gender on pregabalin plasma concentrations.

Kidney failure

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 pregabalin is excreted primarily by the kidneys, patients with renal insufficiency should be given a reduced dose of the drug and an additional dose should be administered after hemodialysis (see section "Dosage and administration", table).

Liver failure

Specific pharmacokinetic studies have not been conducted in patients with hepatic impairment. Since pregabalin is not extensively metabolized and is excreted primarily unchanged in the urine, hepatic impairment is unlikely to have a significant effect on 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.

Following oral administration of pregabalin to children in the fasted state, plasma tmax was generally similar across age groups and ranged from 0.5 hours to 2 hours post-dose.

Pregabalin Cmax and area under the concentration-time curve (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 (aged 65 years and over)

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 pregabalin dose (see Dosage and Administration, table).

Breastfeeding period

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 human milk, with mean steady-state concentrations approximately 76% of the maternal plasma concentration. 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 therapy for 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 medicinal product.

Interaction with other medicinal products and other types of interactions

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

In vivo studies and population pharmacokinetic analysis

Therefore, in vivo studies did not show any clinically significant pharmacokinetic interactions between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis demonstrated that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on the clearance of pregabalin.

Oral contraceptives, norethisterone and/or ethinyl estradiol

Co-administration of pregabalin with 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.

During post-marketing surveillance, cases of respiratory failure, coma and death have been reported in patients taking pregabalin in combination with opioids and/or other CNS depressants. Pregabalin is likely to potentiate the cognitive and gross motor impairments caused by oxycodone.

Interactions in elderly patients (aged 65 years and over)

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 pregabalin therapy may require dose adjustment of their antidiabetic medicinal products.

Hypersensitivity reactions

Hypersensitivity reactions, including angioedema, have been reported in the post-marketing setting of pregabalin. If symptoms of angioedema such as facial edema, perioral edema, or upper airway edema 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 falls in elderly patients. There have also been post-marketing reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of this medicinal product.

Vision disorders

In controlled trials, blurred vision was more frequently observed in patients taking pregabalin than in patients taking placebo. In most cases, this phenomenon resolved with continued therapy. In clinical trials in which ophthalmological examinations were performed, the incidence of visual acuity deterioration and visual field changes was higher in patients taking pregabalin compared to patients in the placebo group; the incidence of fundus changes was higher in patients in the placebo group (see section "Pharmacodynamics").

Ocular adverse reactions, including vision loss, blurred vision, or other changes in visual acuity, many of which were transient, have also been reported. These visual symptoms may resolve or improve after discontinuation of pregabalin.

Kidney failure

Cases of renal failure have been reported, which were sometimes reversible after discontinuation of pregabalin.

Severe cutaneous adverse reactions (SCARs)

Cases of TSR, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with a frequency of rare, which can be life-threatening and life-threatening. Patients and physicians should be closely monitored for skin reactions when prescribing Pregabalin-Darnitsa. If signs and symptoms suggestive of these reactions appear, the drug should be discontinued immediately and alternative treatment should be considered.

Withdrawal of concomitant antiepileptic drugs

There is currently insufficient data on whether concomitant antiepileptic drugs can be withdrawn once seizure control is achieved with the addition of pregabalin to therapy in order to switch to pregabalin monotherapy.

Withdrawal symptoms

Convulsions, including status epilepticus and grand mal seizures, may occur during pregabalin therapy or shortly after its discontinuation.

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

Congestive heart failure

Congestive heart failure has been reported in some patients taking pregabalin. This reaction has been observed primarily during the treatment of neuropathic pain with pregabalin 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 neuropathic pain of central origin due to spinal cord injury

During the treatment of central neuropathic pain caused by spinal cord injury, the frequency of adverse reactions in general and CNS adverse reactions, especially drowsiness, was increased. This may be due to the additive effect of concomitant medicinal products (e.g. antispasticity medicinal products) required for the treatment of this condition. This should be taken into account when prescribing pregabalin for this condition.

Respiratory depression

Severe respiratory depression has been reported with pregabalin. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants, and the elderly may be at greater risk of this serious adverse reaction. These patients may require dose adjustment (see Dosage and Administration).

Suicidal thinking and behavior

Suicidal ideation and behavior have been reported in patients treated with antiepileptic drugs for some indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also reported a small increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown, and the available data do not exclude the possibility of an increased risk with pregabalin.

Therefore, patients should be closely monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice if signs of suicidal ideation or behavior emerge.

Lower gastrointestinal dysfunction

There have been reports of events associated with lower gastrointestinal dysfunction (intestinal obstruction, paralytic ileus, constipation) when pregabalin is used together with medicinal products that can cause constipation, such as opioid analgesics. When pregabalin and opioids are used concomitantly, measures should be taken to prevent constipation (especially in elderly patients and younger women).

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, an increased risk of opioid-related mortality was observed in patients receiving pregabalin concomitantly with an opioid 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]) with a trend toward an increased risk at higher doses of pregabalin (> 300 mg, 2.55 aOR [95% CI, 1.24–5.06]).

Misuse, abuse or addiction

There have been reports of misuse, abuse and dependence. The drug should be used with caution in patients with a history of substance abuse; the patient should be monitored for signs of misuse, abuse or dependence on pregabalin (including cases of habituation, exceeding the prescribed dose, drug-seeking behavior).

Encephalopathy

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

Important information about excipients

This medicinal product contains 58.25/116.5/233 mg of lactose monohydrate, therefore it should be used with caution in patients with diabetes mellitus. Patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption syndrome, Lapp lactase deficiency are not recommended to take this medicinal product.

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

Reproductive toxicity has been demonstrated in animal studies. The potential risk to humans is unknown.

The drug should not be used during pregnancy unless absolutely necessary (when the benefit to the mother clearly outweighs the possible risk to the fetus).

Breastfeeding period

Small amounts of pregabalin have been found in the milk of breastfeeding women. Therefore, the use of this medicine in breastfeeding women is not recommended.

Fertility

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

In a clinical study of the effects of pregabalin on sperm motility, healthy male volunteers were administered pregabalin at a dose of 600 mg per day. No effect on sperm motility was observed after 3 months of pregabalin administration.

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

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug may have minor or moderate influence on the ability to drive and use machines. It may cause dizziness and drowsiness, which will affect the ability to drive and use machines. Therefore, patients should be advised to refrain from driving, operating complex machinery, and other potentially hazardous activities until it is known whether this drug affects their ability to perform such activities.

Method of administration and doses

Method of application

Apply regardless of food intake.

This medicine is intended for oral use only.

Doses

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

Neuropathic pain

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 3–7 days, and if necessary, to a maximum dose of 600 mg per 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 of the drug for the treatment of fibromyalgia is 300 to 450 mg per day. Treatment should be initiated at a dose of 75 mg twice a day (150 mg per day). Depending on the effectiveness and tolerability of the drug, the dose can be increased to 150 mg twice a day (300 mg per day) within one week. For patients for whom the use of a dose of 300 mg per day is insufficient, the dose can be increased to 225 mg twice a day (450 mg per day). Although there is a study using a dose of 600 mg per day, there is no evidence that this dose will have an additional advantage; this dose was also worse tolerated. Taking into account dose-dependent adverse reactions, the use of doses above 450 mg per day is not recommended. Since pregabalin is excreted primarily by the kidneys, the dose of the drug 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).

Pregabalin dose adjustment according to renal function

* 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.

Patients with hepatic insufficiency

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

Elderly patients (aged 65 years and over)

Elderly patients may require a reduction in the dose of pregabalin due to impaired 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, no dosage recommendations can be made for this patient population.

Overdose

The most common adverse reactions in pregabalin overdose were drowsiness, confusion, agitation, and restlessness. Convulsions have also been reported. Coma has been reported rarely.

Treatment of pregabalin overdose consists of general supportive measures and may include haemodialysis if necessary (see section 4.2, table).

Adverse reactions

In the clinical trial program of pregabalin, more than 8,900 patients received it, of whom 5,600 were in double-blind, placebo-controlled trials. The most frequently reported adverse reactions were dizziness and somnolence. Adverse reactions were generally mild to moderate in severity. In all controlled trials, the rate of discontinuation due to adverse reactions was 12% in patients receiving pregabalin and 5% in patients receiving 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 - < 1/10), uncommon (≥ 1/1,000 - < 1/100), rare (≥ 1/10,000 - < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

These adverse reactions may also be related to the course of the underlying disease and/or concomitant use of other