Prezel 150

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PREZEL 75 (PREZEL 75) PREZEL 150 (PREZEL 150) PREZEL 300 (PREZEL 300)

Composition:

Active substance: pregabalin;

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

Excipients: pregelatinized starch, talc;

capsule shell: gelatin, purified water, sodium lauryl sulfate, titanium dioxide (E 171), iron oxide red (E 172) (for 75 mg and 300 mg capsules).

Dosage form. Capsules.

Main physicochemical properties:

• 75 mg capsules: hard gelatin capsules, size 4, with a red-brown cap and a cream-colored body.
• 150 mg capsules: hard gelatin capsules, size 2, with a cream-colored cap and body.
• 300 mg capsules: hard gelatin capsules, size 0, with a red-brown cap and a cream-colored body.

Pharmacotherapeutic group. Antiepileptics, other antiepileptic drugs.

ATC code N03AX16.

Pharmacological Properties

Pharmacodynamics

Active substance – pregabalin, which is 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 drug has been demonstrated in clinical trials for the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of the drug in other types of neuropathic pain has not been studied.

Pregabalin was studied in 10 controlled clinical trials lasting up to 13 weeks with a dosing regimen of twice daily, and in trials lasting up to 8 weeks with a dosing regimen of three times daily. Overall, the safety and efficacy profiles for both twice-daily and three-times-daily regimens were similar.

In clinical trials lasting up to 12 weeks, in which the drug was used for the treatment of neuropathic pain, reduction in peripheral and central pain was observed after the first week and persisted throughout the treatment period.

In controlled clinical trials studying 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 those receiving pregabalin and in 18% of those 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 studying centrally mediated 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 lasting 12 weeks with a dosing regimen of twice or three times daily. Overall, the safety and efficacy profiles for both 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 children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study involving 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 "Pharmacokinetics", "Dosage and administration", and "Adverse reactions").

In the 12-week placebo-controlled study, children were administered 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 seizure frequency 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 lasting 56 weeks with a dosing regimen of twice daily. Pregabalin did not show inferiority compared to lamotrigine, based on the 6-month endpoint assessment of seizure freedom. Pregabalin and lamotrigine were equally safe and well tolerated.

Generalized anxiety disorder

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

Reduction in symptoms of generalized anxiety disorder, as assessed by the Hamilton Anxiety Rating Scale (HAM-A), was observed as early as week 1.

In controlled clinical trials (lasting 4–8 weeks), a ≥50% improvement 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. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundus examination with dilated pupils) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity worsened in 6.5% of those in the pregabalin group and in 4.8% of those in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and in 11.7% of those in the placebo group. Fundus changes were observed in 1.7% of patients receiving pregabalin and in 2.1% of those in the placebo group.

Fibromyalgia

The efficacy of the drug Prezel was established in one 14-week double-blind, placebo-controlled, multicenter trial (F1) and in one 6-week randomized withdrawal trial (F2). Patients with a diagnosis of fibromyalgia based on American College of Rheumatology criteria (widespread pain lasting at least 3 months and pain present in 11 or more of 18 specific tender points) were enrolled. The trials demonstrated reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global impression and fibromyalgia impact questionnaire.

Children. A 15-week placebo-controlled trial was conducted in 107 adolescents aged 12–17 years with fibromyalgia, who received Prezel at doses of 75–450 mg/day. Based on the primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured on an 11-point rating scale), numerically greater improvement was observed in patients receiving pregabalin compared to those receiving placebo, but this improvement did not reach statistical significance. The most commonly observed adverse reactions in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics

Pharmacokinetic parameters of pregabalin at steady state were similar in healthy volunteers, patients with epilepsy taking antiepileptic drugs, and patients with chronic pain.

Absorption

Pregabalin is rapidly absorbed after oral administration on an empty stomach, reaching maximum plasma concentration (Cmax) within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥90% and is independent of dose. At steady state, equilibrium is reached within 24–48 hours after multiple dosing. The rate of pregabalin absorption is reduced when taken with food, resulting in approximately a 25–30% decrease in Cmax and prolongation of time to reach maximum concentration (tmax) to approximately 2.5 hours. However, administration of pregabalin with food does not have a clinically significant effect on the extent of absorption.

Distribution

Preclinical studies 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 detected in urine—was 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 in unchanged form, 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 is required for patients with renal impairment or those on hemodialysis (see section "Dosage and administration", Table 1).

Linearity/Non-linearity

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

Gender

Clinical trial data indicate no clinically significant effect of gender on plasma concentrations of pregabalin.

Renal impairment

Pregabalin clearance is directly proportional to creatinine clearance. 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 supplemental dosing is needed after hemodialysis (see section "Dosage and administration", Table 1).

Hepatic impairment

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is excreted predominantly unchanged in urine, it is unlikely that hepatic dysfunction would have a significant effect on plasma concentrations of pregabalin.

Children

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

After oral administration of pregabalin to children on an empty stomach, tmax was generally similar across all age groups, ranging from 0.5 to 2 hours post-dose.

Cmax and area under the concentration-time curve (AUC) values of pregabalin increased linearly with dose in each age group. In children with body weight below 30 kg, AUC values were 30% lower, due to a 43% higher body weight-adjusted clearance in these patients compared to those with body weight ≥30 kg.

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

Population pharmacokinetic analysis showed that creatinine clearance was a significant covariate for oral pregabalin clearance, and body weight was a significant covariate for apparent volume of distribution of oral pregabalin, with this relationship being similar in children and adult patients.

Pregabalin pharmacokinetics have not been studied in patients under 3 months of age (see sections "Pharmacodynamics", "Dosage and administration", and "Adverse reactions").

Elderly patients

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

Lactation period

Pregabalin pharmacokinetics after administration at a dose of 150 mg every 12 hours (daily dose 300 mg) were evaluated in 10 breastfeeding women at least 12 weeks postpartum. Breastfeeding did not affect or had minimal effect on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk, with average steady-state concentrations approximately 76% of maternal plasma concentrations. The calculated infant dose from breast milk (assuming average milk intake of 150 mL/kg/day) from a woman taking pregabalin at 300 mg/day or at the maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the maternal daily dose normalized to mg/kg.

Clinical characteristics.

Indications.

Neuropathic pain

Prezel is indicated for the treatment of peripheral or central neuropathic pain in adults.

Epilepsy

Prezel is indicated in adults as adjunctive therapy for partial seizures with or without secondary generalization.

Generalized anxiety disorder

Prezel is indicated for the treatment of generalized anxiety disorder in adults.

Fibromyalgia

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

Since pregabalin is predominantly excreted 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, clinically significant pharmacokinetic interactions between pregabalin and other drugs are unlikely, and pregabalin is unlikely to be the object of such 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 either medicinal product.

Medicinal products affecting the CNS

Pregabalin may potentiate the effects of ethanol and lorazepam.

During the post-marketing surveillance period, cases of respiratory depression, coma, and fatal outcomes have been reported in patients taking pregabalin together with opioids and/or other medicinal products that depress CNS function. Pregabalin is likely to enhance cognitive and gross motor impairment caused by oxycodone.

Interactions in elderly patients

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

Special precautions for use.

Patients with diabetes

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

Hypersensitivity reactions

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

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 (e.g., falls) in elderly patients. Additionally, post-marketing reports have described cases of loss of consciousness, confusion, and psychiatric disturbances. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of this medicinal product.

Visual disorders

During controlled studies, blurred vision was 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 ophthalmologic examinations, the incidence of decreased visual acuity and visual field changes was higher in patients receiving pregabalin compared to placebo group patients; however, the incidence of fundus changes was higher in the placebo group (see section "Pharmacodynamics").

Post-marketing reports have also described adverse reactions affecting the visual organs, including vision loss, blurred vision, or other changes in visual acuity, many of which were transient. These visual symptoms may resolve or diminish after discontinuation of pregabalin.

Renal impairment

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

Discontinuation of concomitant antiepileptic drugs

There is currently insufficient data on whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved by adding pregabalin, 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, and dizziness, indicating physical dependence. This information should be communicated to the patient prior to initiating therapy.

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

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

Heart failure

Post-marketing reports have described cases of congestive heart failure in some patients taking pregabalin. This reaction was mostly observed during treatment of neuropathic pain in elderly patients with pre-existing cardiovascular disorders. Pregabalin should be used with caution in such patients. This condition may resolve 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 CNS-related effects such as somnolence, increased. This may be related to additive effects of concomitant medications (e.g., antispastic agents) required for treatment of this condition. This should be taken into account when prescribing pregabalin for this indication.

Suicidal thoughts and behavior

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

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

Lower gastrointestinal tract dysfunction

Events related to lower gastrointestinal tract dysfunction (intestinal obstruction, paralytic ileus, constipation) have been reported with pregabalin use in combination with medications that may cause constipation, such as opioid analgesics. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be implemented (especially in women and elderly patients).

Concomitant use with opioids

Caution is recommended when using pregabalin concomitantly with opioids due to the risk of CNS depression (see section "Interaction with other medicinal products and other forms of interaction"). In controlled clinical trials, patients receiving pregabalin together with an opioid had an increased risk of opioid-related death compared to opioid use alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19–2.36]). This increased risk was observed at low pregabalin doses (≤300 mg, aOR 1.52 [95% CI, 1.04–2.22]), and a trend toward higher risk was observed at high pregabalin doses (>300 mg, aOR 2.55 [95% CI, 1.24–5.06]).

Misuse, abuse, or dependence

Cases of misuse, abuse, and dependence have been reported. The drug should be used with caution in patients with a history of substance abuse. Patients should be monitored for signs of misuse, 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 primarily in patients with comorbid conditions that may predispose to encephalopathy.

Lactose intolerance

The drug Prezel contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Use during pregnancy or breastfeeding.

Women of childbearing potential / Contraceptive methods for women and men

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

Pregnancy

Adequate data on pregabalin use in pregnant women are lacking.

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

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

Breastfeeding period

A small amount of pregabalin has been detected in human breast milk. Women who are breastfeeding should be informed that breastfeeding is not recommended during pregabalin use.

Fertility

Clinical data on the effect of pregabalin on female fertility are lacking.

In a clinical study evaluating the effect of pregabalin on sperm motility, healthy male volunteers received pregabalin 600 mg daily. 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 male rat fertility studies, adverse effects on reproductive function and development were observed. The clinical significance of these findings is unknown.

Ability to influence the speed of reactions when driving or operating machinery.

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

Dosage and Administration

Route of Administration

Presel is taken independently of food intake.

This medicinal product is intended for oral use only.

Dosage

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

Neuropathic Pain

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

Epilepsy

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2–3 doses. Depending on individual response and tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week, the dose may be further increased to the maximum of 600 mg per day.

Generalized Anxiety Disorder

The dose, divided into 2 or 3 administrations, may range from 150 to 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 individual response and tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week, the dose may be increased to 450 mg per day. Following an additional week, the dose may be increased to the maximum of 600 mg per day.

Fibromyalgia

The recommended dose of the drug for the treatment of fibromyalgia ranges from 300 to 450 mg per day. Treatment should be initiated at a dose of 75 mg twice daily (150 mg per day). Depending on efficacy and tolerability, the dose may be increased to 150 mg twice daily (300 mg per day) within one week. For patients in whom a dose of 300 mg per day is insufficiently effective, the dose may be increased to 225 mg twice daily (450 mg per day). Although a study has evaluated a dose of 600 mg per day, there is no evidence that this dose provides additional benefit; furthermore, this dose was associated with poorer tolerability. Due to dose-dependent adverse reactions, doses above 450 mg per day are not recommended. Since pregabalin is primarily eliminated by the kidneys, dosage adjustment is necessary in patients with renal impairment.

Discontinuation of Pregabalin

According to current clinical practice, discontinuation of pregabalin therapy should be gradual over at least one week, regardless of the indication (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Renal Impairment

Pregabalin is eliminated from systemic circulation unchanged, predominantly via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage reduction in patients with renal impairment should be individualized as indicated in Table 1, based on creatinine clearance (CLcr) calculated using the 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 should be administered immediately after each 4-hour hemodialysis session (see Table 1).

Table 1

Dosage 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 amount (mg/dose).

• Additional dose means an extra single dose.

Hepatic impairment

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

Geriatric 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 Prezel in children under 18 years of age have not been established. Available information to date is presented in section "Adverse reactions" as well as in sections "Pharmacodynamics" and "Pharmacokinetics"; however, based on this information, no dosing recommendations can be provided for this patient population.

Overdose

Following marketing of the drug, the most commonly reported adverse reactions associated with pregabalin overdose have been somnolence, confusion, agitation, and restlessness. Seizures have also been reported.

Coma has been reported rarely.

Management of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis (see section "Method of administration and dosage", Table 1).

Adverse Reactions

In the clinical development program for pregabalin, over 8,900 patients received the drug, of whom 5,600 participated in double-blind, placebo-controlled studies. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally mild to moderate in severity. In all controlled trials, 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 study medication in the pregabalin group were dizziness and somnolence.

Below are listed all adverse reactions occurring more frequently than with placebo and in more than one patient. These adverse reactions are categorized by organ system 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 not known (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in descending order of severity.

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

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

Additional adverse reactions reported after marketing of the drug are listed below and indicated in italics.

Infections and infestations

Common: nasopharyngitis.

Blood and lymphatic system disorders

Uncommon: neutropenia.

Immune system disorders

Uncommon: hypersensitivity.

Rare: angioedema, allergic reactions, anaphylactoid reactions.

Metabolism and nutrition disorders

Common: increased appetite.

Uncommon: loss of appetite, hypoglycemia.

Psychiatric disorders

Common: euphoric mood, confusion, irritability, disorientation, insomnia, decreased libido.

Uncommon: hallucinations, panic attacks, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood changes, depersonalization, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition.

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, psychiatric 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 ulceration, exophthalmos, oculomotor muscle paralysis, iritis, keratoconjunctivitis, miosis, night blindness, ophthalmoplegia, optic nerve atrophy, optic disc edema, ptosis, uveitis.

Ear and labyrinth disorders

Common: vertigo.

Uncommon: hyperacusis.

Cardiac disorders

Uncommon: tachycardia, first-degree atrioventricular block, sinus bradycardia, congestive heart failure.

Rare: 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, hiccup, 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 hemorrhage.

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

Hepatobiliary disorders

Uncommon: increased liver enzymes*.

Rare: jaundice.

Very rare: liver failure, hepatitis.

Skin and subcutaneous tissue disorders

Common: pressure ulcers.

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

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, breast discharge, breast enlargement, gynecomastia, cervicitis, balanitis, epididymitis.

General disorders and administration site conditions

Common: peripheral edema, edema, gait disturbance, fall, feeling of intoxication, unusual feelings, fatigue.

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

Rare: granuloma, self-harm, 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 white blood cell count.

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

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

Children. 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 studies of adult patients with epilepsy. The most commonly observed adverse events in the 12-week pregabalin treatment study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis (see sections "Pharmacodynamics", "Pharmacokinetics", and "Dosage and Administration").

Suspected adverse reactions reporting. Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30°C, in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging.

10 capsules per blister. 3 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Ind-Swift Limited, India.

Manufacturer's address and site of operations.

Off. NH-21, Village Jawaharpur, Tehsil Dera Bassi, District S.A.S. Nagar (Mohali), IN-140507, India.