Bapre

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

Composition:

Active substance: pregabalin;

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

Excipients: mannite (E 421), maize starch, talc;

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

Pharmaceutical form. Capsules.

Main physicochemical properties:

• 75 mg capsules: hard gelatin capsules, size 4, with reddish-brown cap / white body, marked with "140" on the cap and "J" on the body in black ink, filled with white or almost white powder.
• 150 mg capsules: hard gelatin capsules, size 2, with white cap / white body, marked with "142" on the cap and "J" on the body in black ink, filled with white or almost white powder.
• 300 mg capsules: hard gelatin capsules, size 0, with reddish-brown cap / white body, marked with "145" on the cap and "J" on the body in black ink, filled with white or almost white powder.

Pharmacotherapeutic group. Antiepileptic agents. Other antiepileptic agents.

ATC code N03A X16.

Pharmacological Properties.

Pharmacodynamics.

The active substance, pregabalin, 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 studies for the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of pregabalin in other types of neuropathic pain has not been studied.

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

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

In controlled clinical trials of peripheral neuropathic pain, a 50% improvement on the pain rating scale was observed in 35% of patients receiving pregabalin and in 18% of patients receiving placebo. Among patients who did not experience somnolence, such improvement was observed in 33% of those receiving pregabalin and in 18% of those receiving placebo. Among patients who experienced somnolence, the proportion of responders was 48% in the pregabalin group and 16% in the placebo group.

In a controlled clinical trial of central neuropathic pain, a 50% improvement on the pain rating scale was observed in 22% of patients receiving pregabalin and in 7% of patients receiving placebo.

Epilepsy

Adjunctive therapy. Pregabalin was studied in 3 controlled clinical trials of 12 weeks' duration with a dosing regimen of twice or three times daily. Overall, the safety and efficacy profiles for the twice-daily and three-times-daily regimens were similar.

Reduction in seizure frequency was observed as early as the first week.

Children. The efficacy and safety of pregabalin as adjunctive therapy 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 trial involving 295 children aged 4 to 16 years, designed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and 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 trial, children received pregabalin at 2.5 mg/kg/day (maximum 150 mg/day), pregabalin at 10 mg/kg/day (maximum 600 mg/day), or placebo. A reduction in partial seizures of at least 50% compared to baseline was observed in 40.6% of patients receiving pregabalin at 10 mg/kg/day (p=0.0068 vs placebo), in 29.1% of patients receiving pregabalin at 2.5 mg/kg/day (p=0.2600 vs placebo), and in 22.6% of those receiving placebo.

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

Generalized anxiety disorder

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

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

In controlled clinical trials (4–8 weeks' duration), a reduction of at least 50% in total HAM-A score from baseline to endpoint was observed in 52% of patients receiving pregabalin and in 38% of patients receiving placebo.

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 fundoscopic 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 patients receiving placebo. Fundoscopic changes were observed in 1.7% of patients receiving pregabalin and in 2.1% of patients receiving placebo.

Fibromyalgia

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

Children. A 15-week placebo-controlled trial was conducted in 107 children aged 12–17 years with fibromyalgia, who received pregabalin at doses of 75–450 mg/day. The primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured on an 11-point rating scale) showed numerically greater improvement in patients receiving pregabalin compared to those receiving placebo, but this improvement did not reach statistical significance. The most commonly reported 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 and reaches maximum plasma concentration (Cmax) within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥ 90% and is dose-independent. Steady-state concentrations are achieved within 24–48 hours with multiple dosing. The rate of pregabalin absorption is reduced when taken with food, resulting in approximately a 25–30% reduction in Cmax and an increase in tmax to approximately 2.5 hours. However, administration of pregabalin with food does not have a clinically significant effect on the extent of its absorption.

Distribution

Preclinical studies have shown that pregabalin crosses the blood-brain barrier in mice, rats, and monkeys. 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—excreted in urine was 0.9% of the administered dose. Racemization of the S-enantiomer of pregabalin to the R-enantiomer did not occur during preclinical studies.

Elimination

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

Dose adjustment is required for patients with renal impairment or patients undergoing hemodialysis (see section "Dosage and administration", table).

Linearity/Non-linearity

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

Gender

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

Renal impairment

Pregabalin clearance is directly proportional to creatinine clearance. Additionally, 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 an additional dose should be administered after hemodialysis (see section "Dosage and administration", table).

Hepatic impairment

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is excreted in urine predominantly unchanged, hepatic impairment is unlikely to 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, the time to reach maximum plasma concentration (tmax) was generally similar across all age groups, ranging from 0.5 to 2 hours after administration.

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

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

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

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 pregabalin clearance after oral administration 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).

Lactation

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 a negligible effect on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk, with mean 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 mother's total daily dose normalized to mg/kg.

Clinical characteristics.

Indications.

Neuropathic pain

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

Epilepsy

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

Generalized anxiety disorder

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

Fibromyalgia

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other 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, it is unlikely that pregabalin would cause or be subject to pharmacokinetic interactions.

In vivo studies and population pharmacokinetic analysis

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

Oral contraceptives, norethisterone and (or) ethinylestradiol

Concomitant administration of pregabalin with oral contraceptives, norethisterone and (or) ethinylestradiol does not affect the steady-state pharmacokinetics of either medicinal product.

Medicinal products affecting the CNS

Pregabalin may potentiate the effects of ethanol and lorazepam. During post-marketing surveillance, cases of respiratory depression, coma, and death have been reported in patients who took pregabalin together with opioids and/or other medicinal products that suppress CNS function. Pregabalin is likely to enhance cognitive and gross motor dysfunction caused by oxycodone.

Interactions in elderly patients

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

Special precautions for use.

Patients with diabetes mellitus

According to current clinical practice, some patients with diabetes mellitus who experience weight gain during pregabalin therapy may require adjustment of their antidiabetic medication doses.

Hypersensitivity reactions

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

Rare cases of serious skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which may be life-threatening or fatal, have been reported during treatment with pregabalin. Patients should be informed about signs and symptoms of skin reactions and monitored closely. If signs or symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative therapy considered (if necessary).

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

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

Visual disorders

During controlled clinical trials, blurred vision occurred more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this effect resolved with continued therapy. In clinical studies involving ophthalmological examinations, the incidence of decreased visual acuity and visual field changes was higher in patients treated with pregabalin compared to placebo; however, the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacodynamics").

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

Renal impairment

Cases of renal impairment, sometimes reversible upon discontinuation of pregabalin, have been reported.

Discontinuation of concomitant antiepileptic drugs

There is insufficient data regarding whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved by adding pregabalin, with the aim of switching to pregabalin monotherapy.

Withdrawal symptoms

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

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

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

Heart failure

Post-marketing reports have described cases of congestive heart failure in some patients taking pregabalin. This reaction was primarily 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 managing this condition. This factor should be considered when prescribing pregabalin for this indication.

Respiratory depression

Serious respiratory depression has been reported in association with pregabalin use. Patients with impaired respiratory function, respiratory or neurological disorders, renal impairment, concomitant use of CNS depressants, and elderly patients may be at higher risk for this serious adverse reaction. Dose adjustment may be required in these patients.

Suicidal ideation and behavior

Cases of suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs for various indications. A meta-analysis of data from randomized, placebo-controlled trials of antiepileptic drugs 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 ideation and behavior, and appropriate treatment considered. Patients (and caregivers) should seek medical help if signs of suicidal ideation or behavior emerge.

Lower gastrointestinal tract dysfunction

Post-marketing reports have described lower gastrointestinal tract dysfunction (intestinal obstruction, paralytic ileus, constipation) associated with pregabalin use, particularly when co-administered with constipating agents 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 prescribing pregabalin concomitantly with opioids due to the risk of CNS depression (see section "Interaction with other medicinal products and other forms of interaction"). In a case-control study of opioid users, an increased risk of opioid-related mortality was observed in patients receiving pregabalin with an opioid 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]), with a trend toward higher risk 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, primarily in patients with comorbid conditions that may predispose to encephalopathy.

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception in women and men

As the potential risk in humans is unknown, women of childbearing potential should use effective contraception.

Pregnancy

Adequate data on pregabalin use in pregnant women are lacking.

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

Bapre 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 advised that breastfeeding is not recommended during pregabalin treatment.

Fertility

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

In a clinical study assessing the effect of pregabalin on sperm motility in healthy male volunteers, pregabalin was administered at a dose of 600 mg 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 fertility studies 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 operating machinery.

Pregabalin may have a slight or moderate influence on the ability to drive vehicles or operate machinery. Pregabalin may cause dizziness and somnolence, thereby affecting the ability to drive vehicles or operate machinery. Therefore, patients should be advised to refrain from driving, 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.

Method of Administration and Dosage

Method of Administration

Bapre should be taken independently of food intake.

This medicinal product is intended for oral use only.

Dosage

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

Neuropathic Pain

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the individual response and tolerability, 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 an additional 7 days.

Epilepsy

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

Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on the individual response and tolerability, 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. After an additional week, the dose may be increased to the maximum of 600 mg per day.

Fibromyalgia

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

Discontinuation of Pregabalin

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

Renal Impairment

Pregabalin is excreted from systemic circulation unchanged, predominantly via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage should be individually adjusted in patients with renal impairment according to the table below, based on creatinine clearance (CLcr) calculated using the following formula:

Pregabalin is effectively removed from plasma by hemodialysis (approximately 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 extra dose of the drug should be administered immediately after each 4-hour hemodialysis session (see table).

Dosage Adjustment of Pregabalin According to Renal Function

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

• Additional dose means an extra single dose.

Hepatic impairment

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

Elderly patients

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

Children

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

Overdose

Since the drug has been marketed, the most commonly reported adverse reactions following pregabalin overdose have been somnolence, confusion, agitation, and restlessness. Seizures have also been reported.

Coma has been reported rarely.

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

Adverse Reactions

In the clinical development program for pregabalin, over 8900 patients received the drug, including 5600 participants in double-blind, placebo-controlled trials. 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, categorized by organ system and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency 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 such as somnolence (see section "Special Warnings and Precautions for Use").

Additional adverse reactions reported after marketing authorization are listed below and indicated in italics.

Infections and infestations

Common: nasopharyngitis.

Blood and lymphatic system disorders

Uncommon: neutropenia.

Immune system disorders

Uncommon: hypersensitivity.

Rare: angioedema, allergic reactions, anaphylactoid reactions.

Metabolism and nutrition disorders

Common: increased appetite.

Uncommon: loss of appetite, hypoglycemia.

Psychiatric disorders

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

Uncommon: hallucinations, panic attacks, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood changes, depersonalization, word-finding difficulty, abnormal 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, sedation, balance disorder, lethargy.

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

Rare: convulsions, 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, parkinsonism.

Eye disorders

Common: blurred vision, diplopia, conjunctivitis.

Uncommon: peripheral vision loss, visual disturbance, eye swelling, visual field defects, reduced 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, brightness of vision, anisocoria, corneal ulcer, exophthalmos, oculomotor paralysis, iritis, keratoconjunctivitis, miosis, night blindness, ophthalmoplegia, optic nerve atrophy, optic disc edema, ptosis, uveitis.

Ear and labyrinth disorders

Common: vertigo.

Uncommon: hyperacusis.

Cardiac disorders

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

Rare: prolonged QT interval, sinus tachycardia, sinus arrhythmia.

Vascular disorders

Uncommon: arterial hypotension, arterial hypertension, flushing, hyperemia, cold sensation in extremities.

Respiratory, thoracic and mediastinal disorders

Common: pharyngolaryngeal pain.

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

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

Frequency not known: respiratory depression.

Gastrointestinal disorders

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

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

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

Hepatobiliary disorders

Uncommon: increased liver enzymes*.

Rare: jaundice.

Very rare: liver failure, hepatitis.

Skin and subcutaneous tissue disorders

Common: pressure ulcers.

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

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

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 delayed, 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 drunk, unusual feelings, fatigue.

Uncommon: generalized edema, facial swelling, chest tightness, pain, hot flushes, thirst, chills, malaise, weakness, abscess, lipodermatosclerosis, photosensitivity reactions.

Rare: granuloma, self-harm, retroperitoneal fibrosis, shock.

Investigations

Common: weight gain.

Uncommon: increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, weight loss.

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, flu-like symptoms, convulsions, nervousness, depression, pain, hyperhidrosis, and dizziness, suggesting physical dependence. This information should be communicated to the patient prior to initiating therapy.

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

Children. The safety profile of pregabalin observed in three studies involving pediatric patients with partial seizures with or without secondary generalization (a 12-week efficacy and safety study in patients with partial seizures, n=295; a pharmacokinetic and tolerability study, n=65; and a 1-year open-label safety study, n=54) was similar to that observed in adult epilepsy studies. The most commonly reported adverse reactions 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 reaction reporting. Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25°C, in a place inaccessible to children.

Packaging.

10 capsules per blister; 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer. Hetero Labs Limited.

Manufacturer's location and address of place of business.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.