Zonik

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZONIK (ZONIK®)

Composition:

Active substance: pregabalin;

1 hard capsule contains 25 mg or 50 mg of pregabalin;

Excipients: pregelatinized starch, magnesium stearate, hard gelatin capsule (gelatin, purified water, titanium dioxide (E 171), sodium lauryl sulfate).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

25 mg hard capsules: hard gelatin capsules size №4 with a white body and a white cap, containing powder from white to almost white;

50 mg hard capsules: hard gelatin capsules size №4 with a white body and a white cap, containing powder from white to almost white.

Pharmacotherapeutic group. Antiepileptic agents. Other antiepileptic agents. Pregabalin. ATC code N03AX16.

Pharmacological properties.

Pharmacodynamics.

The active substance, pregabalin, is a structural analogue of gamma-aminobutyric acid

[(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.

Pregabalin is effective in patients with diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of pregabalin has not been studied in other types of neuropathic pain.

Safety and efficacy profiles of pregabalin treatment for up to 13 weeks with a twice-daily dosing regimen and for up to 8 weeks with a three-times-daily regimen are similar.

When pregabalin is used to treat neuropathic pain for up to 12 weeks, reduction in peripheral and central pain is observed after the first week and maintained throughout the treatment period.

• Epilepsy.

Adjunctive therapy. Safety and efficacy profiles of pregabalin were similar with 12-week treatment using twice-daily or three-times-daily dosing regimens. 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 in adolescents have not been established. Adverse reactions observed in patients aged 3 months to 16 years with partial seizures were similar to those in adults. Pyrexia and upper respiratory tract infections were observed more frequently in children aged 3 months to 16 years than in adult patients with epilepsy (see sections "Posology and method of administration", "Adverse reactions", and "Pharmacokinetics").

Monotherapy (in patients with newly diagnosed disease). Pregabalin and lamotrigine were equally safe and well tolerated.

• Generalized anxiety disorder.

Reduction in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Rating Scale (HAM-A) was observed as early as the first week of pregabalin treatment.

• Fibromyalgia.

Studies demonstrated reduction in pain on the visual analogue scale. Additional improvement was demonstrated by patient global assessment and fibromyalgia impact questionnaire.

Children. The most commonly observed adverse reactions in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics.

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

Absorption.

Pregabalin is rapidly absorbed after oral administration on an empty stomach 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. Steady-state concentrations are achieved within 24–48 hours after repeated administration. The rate of pregabalin absorption 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, co-administration with food does not have a clinically significant effect on the extent of absorption.

Distribution.

Pregabalin crosses the blood-brain barrier in mice, rats, and monkeys. It has been shown to cross the placenta in rats and to be 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 N-methylated metabolite of pregabalin—the main metabolite detected in urine—accounted for 0.9% of the administered dose. During preclinical studies, no racemization of the S-enantiomer of pregabalin to the R-enantiomer was observed.

Excretion.

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 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. The inter-patient variability in pregabalin pharmacokinetics is low (< 20%). Pharmacokinetics after multiple dosing can be predicted from data obtained after single-dose administration. Therefore, routine monitoring of plasma pregabalin concentrations 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 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 required 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 predominantly unchanged in urine, hepatic impairment is unlikely to have a significant effect on plasma concentrations of pregabalin.

Children.

The pharmacokinetics of pregabalin have been studied in children with epilepsy. After oral administration of pregabalin on an empty stomach, the time to reach maximum plasma concentration in children ranged from 0.5 to 2 hours post-dose.

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

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

Creatinine clearance was identified as a significant covariate for oral pregabalin clearance, and body weight was a significant covariate for the apparent volume of distribution of oral pregabalin, with this relationship being similar in children and adult patients.

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

Elderly patients.

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

Breast-feeding.

Breast-feeding had no effect or only a minor effect on the pharmacokinetics of pregabalin when administered at a dose of 150 mg every 12 hours (daily dose 300 mg). Pregabalin passes into breast milk, with average steady-state concentrations in breast milk being 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 the maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the maternal daily dose normalized to mg/kg.

Clinical characteristics.

Indications.

Neuropathic pain.

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

Epilepsy.

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

Generalized anxiety disorder.

Zonic 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.

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 showed that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate do not have a clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and (or) ethinylestradiol.

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

Medicinal products affecting the CNS.

Pregabalin may enhance the effects of ethanol and lorazepam. Cases of respiratory depression, coma, and fatal outcomes 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 basic 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 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.

Severe cutaneous adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been rarely reported with pregabalin treatment. These reactions can be life-threatening or fatal. When prescribing the medicinal product Zonik to patients, they should be informed about the signs and symptoms, and skin reactions should be closely monitored. If signs or symptoms indicating these reactions occur, pregabalin should be discontinued immediately and alternative treatment should be 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 (falls) in elderly patients. Cases of loss of consciousness, confusion, and psychiatric disturbances have also been reported. 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 observed more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this phenomenon 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 group patients; however, the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacodynamics").

Adverse reactions related to the eye, including vision loss, blurred vision, or other changes in visual acuity, have also been reported, 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 is insufficient data on whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved with the addition of pregabalin, to switch to pregabalin monotherapy.

Heart failure.

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

Treatment of central neuropathic pain due to spinal cord injury.

During treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly those affecting the central nervous system and especially somnolence, increased. This may be related to additive effects of concomitant medications (e.g., antispastic agents) required for managing this condition. This should be taken into account when prescribing pregabalin for this indication.

Respiratory depression.

Severe respiratory depression has been reported in association with pregabalin use. Patients with impaired respiratory function, respiratory disorders, neurological disorders, renal impairment, concomitant use of CNS depressants, and elderly patients may be at higher risk of this serious adverse reaction. Dose adjustments may be required for such patients (see section "Dosage and administration").

Suicidal risk.

Cases of suicidal thoughts/behaviour/acts have been reported in patients receiving antiepileptic drugs (including pregabalin) for various indications (see section "Adverse reactions"). A meta-analysis of data from randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal behaviour. The mechanism underlying this risk is unknown. In the post-marketing period, cases of suicidal thoughts/behaviour have been observed in patients receiving pregabalin (see section "Adverse reactions"). An epidemiological study using a self-controlled study design (comparing treatment periods with non-treatment periods within the same individual) demonstrated an increased risk of new-onset suicidal behaviour and suicide death in patients taking pregabalin.

Therefore, patients should be closely monitored for signs of suicidal thoughts/behaviour/acts, and appropriate treatment should be considered. If such signs occur, patients (and caregivers) should seek immediate medical help. Discontinuation of pregabalin therapy should be considered in cases of suicidal thoughts/behaviour.

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 co-administered with medications that may cause constipation, such as opioid analgesics. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be implemented (especially in women and elderly patients).

Concomitant use with opioids.

Pregabalin should be prescribed with caution when used concomitantly with opioids due to the risk of CNS depression (see section "Interaction with other medicinal products and other forms of interaction"). A retrospective study demonstrated that patients taking pregabalin concomitantly with opioids had an increased risk of opioid-related mortality compared to opioid use alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19–2.36]). This increased risk was observed with low doses of pregabalin (≤ 300 mg, aOR 1.52 [95% CI, 1.04–2.22]), and a trend toward higher risk was observed with high doses of pregabalin (> 300 mg, aOR 2.51 [95% CI 1.24–5.06]).

Misuse, abuse, or dependence.

Pregabalin may cause drug dependence, which may occur even at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance abuse may be at higher risk of misuse, abuse, and dependence when using pregabalin, and therefore this medicinal product should be used with caution in such patients. The risk of misuse, abuse, or dependence should be carefully assessed before prescribing pregabalin.

Patients receiving pregabalin therapy should be monitored for symptoms of misuse, abuse, or dependence, such as development of tolerance, dose escalation, and drug-seeking behaviour.

Withdrawal symptoms.

Withdrawal symptoms have been observed after discontinuation of short-term or long-term pregabalin therapy. Reported symptoms include insomnia, headache, nausea, anxiety, diarrhoea, flu-like syndrome, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness. The occurrence of withdrawal symptoms after stopping pregabalin may indicate drug dependence (see section "Adverse reactions***"). This information should be communicated to the patient prior to initiating therapy. If pregabalin needs to be discontinued, it is recommended to do so gradually over at least 1 week, regardless of the indication (see section "**Dosage and administration").

Seizures, including status epilepticus and generalized tonic-clonic 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.

Encephalopathy.

Cases of encephalopathy have been reported, primarily in patients with concomitant conditions that may predispose to encephalopathy.

Women of childbearing potential/contraception.

Pregabalin use during the first trimester of pregnancy may cause serious congenital malformations (CM) in the unborn child. The medicinal product Zonik should not be used during pregnancy except when the therapeutic benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during pregabalin therapy (see section "Pregnancy and breastfeeding").

Excipients.

This medicinal product contains less than 1 mmol of sodium per dose, i.e., essentially "sodium-free".

Pregnancy and breastfeeding.

Women of childbearing potential/contraception.

Women of childbearing potential should use effective contraception.

Pregnancy.

Animal studies have demonstrated reproductive toxicity. Pregabalin has been shown to cross the placenta in rats. Pregabalin may cross the human placenta.

Serious congenital malformations (CM).

Data from a Scandinavian observational study involving more than 2700 pregnant women exposed to pregabalin during the first trimester demonstrated a higher prevalence of serious CMs among children (live or stillborn) exposed to pregabalin in utero compared to unexposed children (5.9% vs. 4.1%).

The risk of serious CMs among children exposed to pregabalin in utero during the first trimester of pregnancy was slightly higher compared to unexposed children (adjusted prevalence ratio and 95% confidence interval: 1.14 (0.96–1.35)) and compared to children exposed to lamotrigine (1.29 (1.01–1.65)) or duloxetine (1.39 (1.07–1.82)).

Analysis of specific CMs showed an increased risk for orofacial clefts and defects of the eye, nervous system, or genitourinary system, although the numbers were small and estimates imprecise.

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

Breastfeeding.

Pregabalin passes into human breast milk. The effect of pregabalin on newborns/infants is unknown. A decision should be made whether to discontinue breastfeeding or to discontinue pregabalin therapy, taking into account the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Fertility.

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

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

Ability to affect 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 and thus may impair the ability to drive vehicles or operate machinery. Therefore, patients should be advised to refrain from driving vehicles, operating complex machinery, or engaging in other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform such activities.

Method of administration and dosage.

Method of administration.

Zonik 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 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 patient 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 between 150–600 mg per day. The need for continued therapy should be periodically reassessed.

Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on individual response and patient 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.

Fibromyalgia.

The recommended dose of the drug for the treatment of fibromyalgia ranges from 300–450 mg per day. Treatment should be initiated at a dose of 75 mg twice daily (150 mg per day). Depending on efficacy and tolerability, the dose may be increased to 150 mg twice daily (300 mg per day) within one week. For patients in whom a dose of 300 mg per day is insufficiently effective, the dose may be increased to 225 mg twice daily (450 mg per day). Although a study has evaluated 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 the drug is primarily eliminated via the kidneys, dosage adjustment is necessary in patients with renal impairment.

Discontinuation of pregabalin.

According to current clinical practice, discontinuation of pregabalin therapy should be gradual over at least one week, regardless of the indication (see sections "Special 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 reduction in patients with renal impairment should be individualized as indicated in Table 1, based on creatinine clearance (CLcr), which should be calculated using the appropriate formula.

Pregabalin is effectively removed from plasma by hemodialysis (50% of the drug is removed 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, a supplemental dose of the drug should be administered immediately after each 4-hour hemodialysis session (see Table 1).

* 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 – 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 "Pharmacokinetics").

Children.

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

Overdose.

The most commonly reported adverse reactions following 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, hemodialysis (see section "Dosage and administration", table).

Adverse Reactions

In clinical studies, the most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally mild or moderate in severity.

Below is a list of 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 (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse effects are listed in order of decreasing severity.

The adverse reactions listed 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 incidence of adverse reactions increased, particularly CNS-related adverse reactions, especially somnolence (see section "Special Warnings and Precautions for Use").

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 alterations, depersonalization, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition, suicidal thoughts/behaviour (see section "Special Warnings and Precautions for Use").

Frequency not known: drug dependence.

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: seizures, parosmia, hypokinesia, dysphagia, parkinsonism, hypalgesia, dependence, cerebellar syndrome, cogwheel rigidity, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain–Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders.

Eye disorders.

Common: blurred vision, diplopia, conjunctivitis.

Uncommon: peripheral vision loss, visual disturbance, eye swelling, visual field defects, decreased visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, blepharitis, accommodation disorder, eye hemorrhage, photophobia, retinal edema.

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

Ear and labyrinth disorders.

Common: vertigo.

Uncommon: hyperacusis.

Cardiac disorders.

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

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

Vascular disorders.

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

Respiratory, thoracic and mediastinal disorders.

Common: pharyngolaryngeal pain.

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

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

Frequency not known: respiratory depression.

Gastrointestinal disorders.

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

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

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

Hepatobiliary disorders.

Uncommon: increased liver enzymes*.

Rare: jaundice.

Very rare: hepatic 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, toxic epidermal necrolysis, cold sweat, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail disorders, petechial rash, purpura, pustular rash, skin atrophy, skin necrosis, skin and subcutaneous nodules.

Musculoskeletal and connective tissue disorders.

Common: muscle cramps, arthralgia, back pain, limb pain, neck muscle spasms.

Uncommon: joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness.

Rare: rhabdomyolysis.

Renal and urinary disorders.

Uncommon: urinary incontinence, dysuria, albuminuria, hematuria, kidney stone formation, nephritis.

Rare: renal failure, oliguria, urinary retention, acute renal failure, glomerulonephritis, pyelonephritis.

Reproductive system and breast disorders.

Common: erectile dysfunction, impotence.

Uncommon: sexual dysfunction, ejaculation delay, dysmenorrhea, breast pain, leukorrhea, menorrhagia, metrorrhagia.

Rare: amenorrhea, 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 edema, chest tightness, pain, warmth, thirst, chills, general weakness, malaise, abscess, lipodermatitis, photosensitivity reactions.

Rare: granuloma, self-injury, 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).

After discontinuation of short-term or long-term pregabalin therapy, withdrawal symptoms have been observed. Reported symptoms include insomnia, headache, nausea, anxiety, diarrhea, influenza-like symptoms, seizures, restlessness, depression, suicidal thoughts, pain, hyperhidrosis, and dizziness. These symptoms may indicate drug dependence. This information should be communicated to the patient prior to initiating therapy.

Data on pregabalin discontinuation after long-term use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

Paediatric population. The safety profile of pregabalin observed in clinical trials involving children with partial seizures with or without secondary generalization was similar to that observed in adult epilepsy trials. The most commonly reported adverse reactions were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis (see sections "Paediatric population", "Pharmacodynamics", and "Pharmacokinetics").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

14 capsules in a blister pack. 2 or 4 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and place of business.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.