Lyridjub

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LYRIJUB (LYRIJUB)

Composition:

Active substance: pregabalin;

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

Excipients: lactose monohydrate; maize starch; talc;

Capsule shell composition: gelatin, titanium dioxide (E 171), sodium lauryl sulfate, iron oxide red (E 172) (for 75 mg and 300 mg capsules);

Ink “TekPrint™ SW-9008 Black Ink”: shellac, propylene glycol, iron oxide black (E 172), potassium hydroxide.

Pharmaceutical form. Capsules.

Main physicochemical properties:

• 75 mg capsules: hard gelatin capsules with reddish-brown cap and white or almost white body, size "4", containing white or almost white powder. Marked with "610" in black ink on the body;
• 150 mg capsules: hard gelatin capsules with white or almost white cap and body, size "2", containing white or almost white powder. Marked with "612" in black ink on the body;
• 300 mg capsules: hard gelatin capsules with reddish-brown cap and white or almost white body, size "0", containing white or almost white powder. Marked with "615" in black ink on the body.

Pharmacotherapeutic group. Antiepileptic agents, other antiepileptic agents.

ATC code N03AX16.

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.

Efficacy of the medicinal product 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 twice-daily dosing regimen and in trials of up to 8 weeks duration with a three-times-daily dosing regimen.

Overall, the safety and efficacy profiles for twice-daily and three-times-daily dosing regimens were similar.

In clinical trials of up to 12 weeks duration, in which the medicinal product 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 3 controlled clinical trials of 12 weeks duration with a twice-daily or three-times-daily dosing regimen. Overall, the safety and efficacy profiles for twice-daily and three-times-daily dosing regimens were similar.

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

Paediatric population. The efficacy and safety of pregabalin as adjunctive therapy in epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study including patients aged from 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 an open-label 1-year 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 "Posology and method of administration", "Adverse reactions", and "Pharmacokinetics").

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 seizures 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. Non-inferiority of pregabalin compared to lamotrigine was not achieved 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 6 controlled trials of 4–6 weeks duration, one 8-week trial in elderly patients, and one long-term trial assessing relapse prevention 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 week 1.

In controlled clinical trials (4–8 weeks duration), a ≥50 % improvement in 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 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 patients in the pregabalin group and in 4.8 % of patients 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. Fundoscopic changes were observed in 1.7 % of patients receiving pregabalin and in 2.1 % of patients in the placebo group.

• Fibromyalgia.

The efficacy of Lyricidub was established in one 14-week double-blind placebo-controlled multicentre 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 reduction in pain on the visual analogue scale. Additional improvement was demonstrated by patient global assessment and fibromyalgia impact questionnaire.

Paediatric population. A 15-week placebo-controlled trial was conducted in 107 adolescents aged 12–17 years with fibromyalgia who received Lyricidub 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 numerical rating scale) showed numerically greater improvement in patients receiving pregabalin compared to those receiving placebo, but this improvement did not achieve 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 when administered on an empty stomach and reaches maximum plasma concentrations within 1 hour after single or multiple doses. The calculated oral bioavailability of pregabalin is ≥ 90 % and is dose-independent. At steady state, equilibrium is achieved within 24–48 hours. The absorption rate of pregabalin is reduced when administered with food, resulting in approximately a 25–30 % decrease in maximum concentration (Cmax) and prolongation of 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 demonstrated 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 radiolabelled dose of pregabalin, approximately 98 % of the radioactivity was excreted in urine as unchanged pregabalin. The fraction of the N-methylated derivative 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 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 "Posology and method of administration", Table 1).

Linearity/non-linearity.

The pharmacokinetics of pregabalin are linear across the entire recommended dose range. 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 study results 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 a supplemental dose should be administered after hemodialysis (see section "Posology and method of 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.

Paediatric population.

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) receiving 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 on an empty stomach, the time to reach maximum plasma concentration 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 a 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 paediatric and adult patients.

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

Elderly patients.

Pregabalin clearance tends to decrease with age. This reduction in pregabalin clearance with 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 "Posology and method of administration", Table 1).

Lactation.

The pharmacokinetics of pregabalin were evaluated in 10 lactating women receiving a dose of 150 mg every 12 hours (daily dose 300 mg), at least 12 weeks after delivery. Breastfeeding had no effect or only a negligible effect on the pharmacokinetics of pregabalin. Pregabalin passed into breast milk, with average steady-state concentrations in breast milk being 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 total daily maternal dose normalized to mg/kg.

Clinical characteristics.

Indications.

Neuropathic pain.

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

Epilepsy.

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

Generalized anxiety disorder.

Lyridjub 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 forms of interaction.

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 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 drugs, 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, repeated oral co-administration of pregabalin with oxycodone, lorazepam, or ethanol did not result in clinically significant effects on respiratory function. Cases of respiratory depression, coma, and fatal outcomes have been reported in patients taking pregabalin concomitantly with other medicinal products that depress CNS function, particularly in patients who abuse such substances. Pregabalin is likely to enhance cognitive and gross motor function 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 mellitus.

According to current clinical practice, some diabetic patients whose body weight has increased 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 such as facial swelling, perioral swelling, or swelling of the upper airways occur, pregabalin should be discontinued immediately.

Severe skin adverse reactions.

Rare cases of severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which may be life-threatening or fatal, have been reported in association with pregabalin treatment. When prescribing this medicinal product, patients should be informed about the signs and symptoms, and skin reactions should be closely monitored. If signs or symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative treatment considered (if necessary).

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. Post-marketing reports have also 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 clinical trials, blurred vision was reported more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this phenomenon resolved with continued therapy. In clinical trials involving ophthalmological examinations, the incidence of decreased visual acuity and visual field changes was higher in patients treated with pregabalin compared to those in the placebo group; 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 after discontinuation of pregabalin, have been reported.

Discontinuation of concomitant antiepileptic drugs.

There are insufficient data regarding whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved with the addition of pregabalin to allow transition to monotherapy with pregabalin.

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, suggesting physical dependence. This information should be communicated to patients prior to initiation of therapy.

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

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

Heart failure.

Post-marketing reports have described cases of heart failure in some patients receiving 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 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 those affecting the central nervous system such as somnolence, was increased. This may be related to the additive effects of concomitant medications (e.g., antispasmodic agents) required for 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 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 underlying this risk is unknown, and available data do not exclude the possibility of an 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 emerge, 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 (e.g., 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 concomitantly 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 with caution in patients with a history of substance abuse, and 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 concomitant conditions that may predispose to encephalopathy.

Lactose intolerance.

Lyricub contains lactose. This medicinal product should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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.

Adequate data on the use of pregabalin in pregnant women are lacking.

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

Lyricub 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.

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.

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/day. 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 relevance of these findings is unknown.

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

Pregabalin may have a negligible or moderate effect on the ability to drive or operate machinery. Pregabalin may cause dizziness and somnolence and thereby affect the ability to drive 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.

Lyridjub 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 doses.

Neuropathic pain.

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 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 or 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 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 individual response and tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week of treatment, 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 is 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 1 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 the use of a 600 mg per day dose, there is no evidence that this dose provides additional benefit; furthermore, this dose was associated with poorer tolerability. Considering 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 1 week, regardless of the indication (see sections "Special precautions" 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 should be individually adjusted in patients with renal impairment as indicated in Table 1, based on creatinine clearance (CLcr) calculated using the following 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 of the drug should be administered immediately after each 4-hour hemodialysis session (see Table 1).

Dosage adjustment of pregabalin according to renal function. Table 1.

Creatinine clearance (CLcr) (mL/min)	Total daily dose of pregabalin *		Dosing regimen
	Initial dose (mg/day)	Maximum dose (mg/day)
≥ 60	150	600	Twice or three times daily
≥ 30 – < 60	75	300	Twice or three times daily
≥ 15 – < 30	25–50	150	Once or twice 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).

• Additional dose means an extra single dose.

Hepatic impairment.

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

Geriatric patients.

For elderly patients, dose reduction of pregabalin may be necessary due to reduced renal function (see section "Dosage and administration").

Children.

Safety and efficacy of Lyridjub in children under 18 years of age have not been established. Currently available information is presented in the sections "Adverse reactions", "Pharmacodynamics" and "Pharmacokinetics"; however, based on this information, no dosage 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 included somnolence, confusion, agitation, and restlessness. Seizures have also been reported.

Rare cases of coma have been reported.

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

Adverse Reactions.

In the clinical program investigating 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 or 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 system organ class 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 based on available data). Within each frequency grouping, adverse reactions are listed in order of decreasing 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 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: decreased 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 swings, 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, hypoesthesia, 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 disorder, 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, parkinsonism.

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 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, 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, hypoaesthesia of oral cavity, 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: elevated 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, toxic epidermal necrolysis (TEN), 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, nephrolithiasis, 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, warmth, thirst, chills, general weakness, malaise, abscess, lipodermatitis, 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 blood leukocyte 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 withdrawal after prolonged pregabalin 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 reported adverse events in the 12-week pregabalin treatment study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis (see sections "Dosage and Administration", "Pharmacodynamics", and "Pharmacokinetics").

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

Shelf life. 2 years.

Storage conditions.

Keep out of the reach of children. Store at temperatures not exceeding 25°C.

Packaging.

10 capsules in a blister. 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Jubilant Generics Limited.

Manufacturer's address and place of business.

Village Sikandarpur, Bhainswal, Roorkee-Dehradun Highway, Bhagwanpur, Roorkee District Haridwar, Uttarakhand, IN-247661, India.