Neurokem 100

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEUROKEM 75 (NEUROKEM 75) NEUROKEM 100 (NEUROKEM 100) NEUROKEM 150 (NEUROKEM 150)

Composition:

Active substance: pregabalin;

1 capsule contains 75 mg of pregabalin;

Excipients: pregelatinized starch, talc; gelatin capsule (size № 4): titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172), gelatin, sodium lauryl sulfate, inks TEC SW 9008 – Black ink;

1 capsule contains 100 mg of pregabalin;

Excipients: pregelatinized starch, talc; gelatin capsule (size № 3): titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172), gelatin, sodium lauryl sulfate, inks TEC SW 9008 – Black ink;

1 capsule contains 150 mg of pregabalin;

Excipients: pregelatinized starch, talc; gelatin capsule (size № 2): titanium dioxide (E 171), gelatin, sodium lauryl sulfate, inks TEC SW 9008 – Black ink.

Dosage form. Capsules.

Main physicochemical properties:

75 mg capsules:

Hard gelatin capsule with an opaque orange cap marked with black ink "A009", and an opaque white body marked with black ink "PREG 75"; capsule content: powder from white to almost white.

100 mg capsules:

Hard gelatin capsule with an opaque orange cap marked with black ink "A010", and an opaque orange body marked with black ink "PREG 100"; capsule content: powder from white to almost white.

150 mg capsules:

Hard gelatin capsule with an opaque white cap marked with black ink "A011", and an opaque white body marked with black ink "PREG 150"; capsule content: powder from white to almost white.

Pharmacotherapeutic group.

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 pregabalin 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 the twice-daily and three-times-daily dosing 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 origin 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 patients receiving pregabalin and in 18% of patients in the placebo group. Among patients who experienced somnolence, the proportion of responders was 48% in the pregabalin group and 16% in the placebo group.

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

• Epilepsy.

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

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

Children. The efficacy and safety of pregabalin as an adjunctive treatment for epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study including patients aged from 3 months to 16 years (n=65) were similar to those in adults. Results from a 1-year open-label safety study involving 54 children aged from 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 adults (see sections "Pharmacokinetics", "Dosage and administration", "Adverse reactions").

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 demonstrated non-inferior efficacy 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 according to the Hamilton Anxiety Rating Scale (HAM-A) was observed as early as the first week.

In controlled clinical trials (lasting 4–8 weeks), a ≥50% improvement from baseline to endpoint in total HAM-A score was observed in 52% of patients receiving pregabalin and in 38% of patients in the placebo group.

In 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 dilated fundus examination) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity decreased in 6.5% of patients in the pregabalin group and in 4.8% in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and in 11.7% of patients in the placebo group. Fundus changes were detected in 1.7% of patients receiving pregabalin and in 2.1% of patients in the placebo group.

Pharmacokinetics.

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

Absorption.

Pregabalin is rapidly absorbed after fasting administration and reaches maximum plasma concentrations within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥90% and is dose-independent. At steady state, equilibrium is reached within 24–48 hours after multiple dosing. The absorption rate of pregabalin is reduced when taken with food, resulting in approximately a 25–30% decrease in maximum concentration (Cmax) and prolongation of time to maximum plasma concentration (tmax) to approximately 2.5 hours. However, co-administration of pregabalin with food did 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 radiolabeled pregabalin, approximately 98% of the radioactivity was excreted in urine as unchanged pregabalin. The fraction of the main metabolite, N-methylated derivative of pregabalin, detected in urine, accounted for 0.9% of the administered dose. Preclinical studies showed no racemization of the S-enantiomer of pregabalin to the R-enantiomer.

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").

Dosage 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 from single-dose administration. Therefore, routine monitoring of plasma concentrations of pregabalin is not required.

Gender.

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

Renal impairment.

Pregabalin clearance is directly proportional to creatinine clearance. Additionally, pregabalin is effectively removed from plasma by hemodialysis (after 4 hours of hemodialysis, plasma pregabalin concentration decreases by approximately 50%). Since the drug is primarily eliminated by the kidneys, dosage reduction is required for patients with renal impairment, and supplemental dosing is necessary 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 in urine predominantly unchanged, it is unlikely that hepatic impairment would have a significant effect on plasma concentrations of pregabalin.

Children.

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

After oral administration of pregabalin to children in the fasting state, 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% 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.

Population pharmacokinetic analysis demonstrated 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.

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

Elderly patients.

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

Lactation.

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

Clinical characteristics.

Indications.

Neuropathic pain.

Treatment of peripheral or central neuropathic pain 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.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Since pregabalin is predominantly excreted unchanged in urine, undergoes negligible 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 may cause or be subject to pharmacokinetic interactions.

In vivo studies and population pharmacokinetic analysis.

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 demonstrated 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 agent.

Medicinal products affecting the CNS.

Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, concomitant multiple oral doses of pregabalin with oxycodone, lorazepam, or ethanol did not result in clinically significant effects on respiratory function. During the post-marketing surveillance period, cases of respiratory depression and coma have been reported in patients taking pregabalin together with other medicinal products that depress CNS function. Pregabalin is likely to enhance cognitive and basic motor impairments 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 diabetic patients whose body weight has increased during pregabalin therapy may require adjustment of antidiabetic medication doses.

Hypersensitivity reactions.

Hypersensitivity reactions, including angioedema, have been reported. 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. Cases of loss of consciousness, confusion, and psychiatric disturbances have been reported. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of pregabalin.

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-treated patients; however, the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacodynamics").

Adverse reactions affecting the visual system, including vision loss, blurred vision, or other changes in visual acuity, have been reported, many of which were transient. These visual symptoms may resolve or diminish after discontinuation of pregabalin.

Renal impairment.

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

Discontinuation of concomitant antiepileptic drugs.

There is currently insufficient data on whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved with the addition of 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 symptoms, restlessness, depression, pain, seizures, hyperhidrosis, and dizziness, indicating 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 pregabalin discontinuation after long-term use suggest that the frequency and severity of withdrawal symptoms may depend on the dose.

Heart failure.

Cases of heart failure have been reported in some patients taking pregabalin. This reaction was mostly observed during pregabalin treatment for neuropathic pain in elderly patients with pre-existing cardiovascular disorders. Pregabalin should be used with caution in such patients. This condition may resolve after discontinuation of pregabalin.

Treatment of central neuropathic pain due to spinal cord injury.

During treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly those affecting the central nervous system (especially somnolence), increased. This may be related to the additive effects of concomitant medications (e.g., antispastic agents) required for the management 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 observed 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 possible increased risk with pregabalin use.

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

Worsening of lower gastrointestinal tract function.

Post-marketing reports have described events related to worsening of lower gastrointestinal tract function (such as intestinal obstruction, paralytic ileus, constipation) with pregabalin use, particularly when used concomitantly with medications that may cause constipation, such as opioid analgesics. When pregabalin is used together with opioids, preventive measures for constipation should be implemented (especially in women and elderly patients).

Misuse, abuse, or dependence.

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

Use during pregnancy or breastfeeding.

Women of childbearing potential / Contraception in women and men.

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

Pregnancy.

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

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

Pregabalin should not be used during pregnancy except in exceptional cases where the benefit to the 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 treatment with pregabalin.

Reproductive function.

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

In a clinical study assessing the effect of pregabalin on sperm motility, healthy male participants received pregabalin 600 mg daily. After 3 months of treatment, no effect on sperm motility was observed.

Fertility studies demonstrated a negative effect on female rats' reproductive function and a negative effect on male rats' reproductive function and development. The clinical relevance of these findings is unknown.

Effect on ability to drive and use machines.

Pregabalin may have a slight or moderate influence on the ability to drive and use machines. The drug may cause dizziness and somnolence and may impair the ability to drive and operate machinery. Therefore, patients should be advised to refrain from driving or 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.

The medication 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 2–3 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 an additional 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 increased to the maximum of 600 mg per day.

Generalized anxiety disorder.

The dose, divided into 2–3 doses, may range from 150–600 mg per day. The need for continued 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 of administration, the dose may be increased to 450 mg per day. After an additional week, the dose may be increased to the maximum of 600 mg per day.

Discontinuation of pregabalin.

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

Renal impairment.

Pregabalin is eliminated from systemic circulation in unchanged form, primarily via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage should be individually adjusted in patients with renal impairment as indicated in Table 1, based on creatinine clearance (CLcr), which is 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 extra dose of the drug should be administered immediately after each 4-hour hemodialysis session (see Table 1).

Table 1

Dosage adjustment of pregabalin according to renal function

Creatinine clearance (CLcr) (mL/min)	Total daily dose of pregabalin *		Dosing regimen
	Initial dose (mg/day)	Maximum dose (mg/day)
≥ 60	150	600	2–3 times daily
≥ 30 – < 60	75	300	2–3 times daily
≥ 15 – < 30	25–50**	150	1–2 times daily
< 15	25	75	Once daily
Additional dose after hemodialysis (mg)
	25	100	Single dose+

* 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).

• Single dose – an additional single dose.

** Administer pregabalin in the appropriate dosage.

Hepatic impairment.

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

Elderly patients.

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

Children.

Safety and efficacy of the drug in children under 18 years of age have not been established. Available data are presented in the section "Adverse reactions" and in sections "Pharmacodynamics" and "Pharmacokinetics"; however, based on these data, no dosing recommendations can be provided for this patient group.

Overdose.

Following market release, the most commonly reported adverse reactions in cases of pregabalin overdose were 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 1).

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 of mild or moderate 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 system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse effects are listed in descending order of severity.

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

During treatment of central neuropathic pain due to spinal cord injury, the overall frequency of adverse reactions increased, particularly CNS-related adverse reactions 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, excitement, depression, depressed mood, elevated mood, aggression, mood alterations, 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, mental impairment, 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, ocular hemorrhage, photophobia, retinal edema.

Rare: vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, brightness of vision, anisocoria, corneal ulcer, exophthalmos, oculomotor nerve paralysis, iritis, keratoconjunctivitis, miosis, night blindness, ophthalmoplegia, optic nerve atrophy, optic disc edema, ptosis, uveitis.

Ear and labyrinth disorders.

Common: vertigo.

Uncommon: hyperacusis.

Cardiac disorders.

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

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

Vascular disorders.

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

Respiratory, thoracic and mediastinal disorders.

Common: pharyngolaryngeal pain.

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

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

Gastrointestinal disorders.

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

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

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

Hepatobiliary disorders.

Uncommon: increased liver enzymes*.

Rare: jaundice.

Very rare: liver failure, hepatitis.

Skin and subcutaneous tissue disorders.

Common: pressure ulcers.

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

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

Musculoskeletal and connective tissue disorders.

Common: muscle spasms, 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, galactorrhea, breast enlargement, gynecomastia, cervicitis, balanitis, epididymitis.

General disorders and administration site conditions.

Common: peripheral edema, edema, gait disturbance, falls, feeling drunk, unusual sensations, fatigue.

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

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

Investigations.

Common: weight increased.

Uncommon: increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase, 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 were observed after discontinuation of short-term or long-term pregabalin therapy. Reported reactions included insomnia, headache, nausea, anxiety, diarrhea, flu-like symptoms, 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 suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.

Children. The safety profile of pregabalin observed in two studies involving pediatric patients (a pharmacokinetic and tolerability study, n=65; a 1-year open-label safety study, n=54) was similar to that observed in adult clinical trials (see sections "Pharmacodynamics", "Pharmacokinetics", and "Dosage and Administration").

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

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 capsules per blister, 1 blister per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Alkem Laboratories Ltd.

Manufacturer's address and location of its business operations.

167 Mahatma Gandhi, Udhyog Nagar, Dabhel, Daman, 396210, India.