Pregamma

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

Composition:

Active substance: pregabalin;

1 hard capsule contains 25 mg or 50 mg or 75 mg or 150 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 characteristics:

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

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

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

150 mg hard capsules: hard gelatin capsules, size № 2, with opaque white cap and body, containing powder from white to almost white.

Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs. 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.

The safety and efficacy profiles of pregabalin treatment have been shown to be similar with a dosing regimen of twice daily for up to 13 weeks and three times daily for up to 8 weeks.

When used for the treatment of neuropathic pain over a 12-week course, reduction in peripheral and central pain was observed after the first week and persisted throughout the treatment period.

Epilepsy

Adjunctive therapy

The safety and efficacy profiles of pregabalin were similar with 12-week treatment regimens administered twice daily or three times daily. 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 patients aged 3 months to 16 years with partial seizures were similar to those in adults. However, pyrexia and upper respiratory tract infections were reported more frequently in children aged 3 months to 16 years than in adult patients with epilepsy (see sections "Pharmacokinetics", "Dosage and administration", and "Adverse reactions").

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, as measured by the Hamilton Anxiety Rating Scale (HAM-A), was observed as early as the first week of pregabalin treatment.

Fibromyalgia

Studies demonstrated a reduction in pain assessed by the visual analogue scale. Additional improvement was shown by patient global impression 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, reaching maximum plasma concentration (Cmax) within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥ 90% and is dose-independent. Steady-state concentrations are achieved within 24–48 hours with repeated dosing. The rate of pregabalin absorption is reduced when administered with food, resulting in approximately a 25–30% decrease in Cmax and prolongation of the time to reach maximum plasma concentration (tmax) to approximately 2.5 hours. However, co-administration with food did 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 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 N-methylated metabolite of pregabalin—the primary metabolite detected in urine—was 0.9% of the administered dose. Racemization of the S-enantiomer of pregabalin to the R-enantiomer did not occur during preclinical studies.

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 and for patients on hemodialysis (see section "Dosage and 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 from 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 in patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Dosage and administration", Table 1).

Hepatic impairment

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is excreted predominantly unchanged in urine, 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, tmax ranged from 0.5 to 2 hours post-dose.

Cmax and area under the plasma concentration-time curve (AUC) 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; this relationship was similar in children and adult patients.

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

Elderly patients

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

Lactation period

Breastfeeding did not affect or had a negligible effect on the pharmacokinetics of pregabalin administered at a dose of 150 mg every 12 hours (daily dose 300 mg). Pregabalin passes into breast milk, with an average steady-state concentration approximately 76% of the maternal plasma concentration. The calculated infant dose via breast milk (assuming average milk intake of 150 mL/kg/day) from a woman taking pregabalin at a daily dose of 300 mg or the maximum dose of 600 mg per day is 0.31 mg/kg/day or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the maternal daily dose normalized to milligrams per kilogram.

Clinical characteristics.

Indications.

Neuropathic pain

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

Epilepsy

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

Generalized anxiety disorder

Pregamma 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 interactions.

Since pregabalin is predominantly excreted unchanged in urine, undergoes minimal metabolism in humans (≤ 2% of the dose is excreted in urine as metabolites), does not inhibit the metabolism of other drugs in vitro, and does not bind to plasma proteins, it is unlikely that pregabalin would cause pharmacokinetic interactions or be the subject of such 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 have no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and (or) ethinylestradiol

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

Medicinal products affecting the CNS

Pregabalin may enhance the effects of ethanol and lorazepam. Cases of respiratory depression, coma, and fatal outcomes have been reported in patients taking pregabalin together with opioids and/or other medicinal products that depress CNS function. Pregabalin is likely to enhance cognitive and gross motor 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

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

Hypersensitivity reactions

Cases of 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 skin adverse reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been rarely reported in association with pregabalin treatment, which may be life-threatening or fatal. When prescribing the medicinal product Pregamma, patients should be informed about signs and symptoms and closely monitored for skin reactions. 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 (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 studies, blurred vision was observed more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this phenomenon resolved with continued therapy. In clinical trials involving ophthalmological examinations, the incidence of decreased visual acuity and visual field changes was higher in patients receiving pregabalin compared to placebo group patients; however, the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacodynamics").

Adverse reactions related to the visual organs, including vision loss, blurred vision, or other changes in visual acuity, have also 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 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

Heart failure has been observed in some patients taking pregabalin. This reaction was mostly reported during treatment of neuropathic pain in elderly patients with pre-existing cardiovascular disorders. Pregabalin should be used with caution in such patients. This phenomenon 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 frequency of adverse reactions, particularly those affecting the central nervous system (CNS), such as 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 diseases, neurological disorders, renal impairment, those receiving concomitant CNS depressants, and elderly patients may be at higher risk of this serious adverse reaction. Dose adjustment may be required for such patients (see section "Dosage and administration").

Suicidal risk

Cases of suicidal thoughts/behaviour have been reported in patients receiving antiepileptic drugs for various indications. Meta-analysis of data from randomized placebo-controlled antiepileptic drug trials also showed a small increased risk of suicidality. The mechanism of this risk is unknown. During 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-related death in patients taking pregabalin.

Therefore, patients should be closely monitored for signs of suicidal thoughts/behaviour, 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.

Lower gastrointestinal tract dysfunction

Post-marketing reports have described events related to lower gastrointestinal tract dysfunction (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 taken (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-dose pregabalin (≤ 300 mg, aOR 1.52 [95% CI, 1.04–2.22]), and a trend toward higher risk was observed with high-dose pregabalin (> 300 mg, aOR 2.51 [95% CI 1.24–5.06]).

Medication 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 taking 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 before starting 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 epileptic status 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, occurring predominantly in patients with concomitant conditions that may provoke 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 Pregamma should not be used during pregnancy except when clearly necessary (i.e., only when the 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 or breastfeeding").

Excipients

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

Pregnancy or 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 who used pregabalin during the first trimester showed a higher prevalence of serious CMs among children (liveborn or stillborn) exposed to pregabalin in utero compared to children not exposed (5.9% vs. 4.1%).

The risk of serious CMs in children exposed to pregabalin in utero during the first trimester of pregnancy was slightly higher compared to children not exposed (adjusted prevalence ratio and 95% CI: 1.14 (0.96–1.35)) and compared to the population exposed to lamotrigine (1.29 (1.01–1.65)) or duloxetine (1.39 (1.07–1.82)).

Analysis of specific CMs showed a higher risk for orofacial clefts and defects of the eyes, nervous system, or urogenital system, although the numbers were small and estimates imprecise.

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

Period of breastfeeding

Pregabalin passes into human breast milk. The effect of pregabalin on newborns/infants is unknown. A decision must 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 mother.

Fertility

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

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

In fertility studies in female rats, adverse effects on reproductive function were observed. In fertility studies in male rats, adverse effects on reproductive function and development were also 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 slight or moderate influence on the ability to drive or operate machinery. Pregabalin may cause dizziness and somnolence, thereby affecting 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

Take the medication Pragma 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 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 doses, may range from 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 is 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. Given dose-dependent adverse reactions, doses above 450 mg per day are not recommended. Since the drug is primarily eliminated by the kidneys, dosage adjustment is required in patients with impaired renal function.

Discontinuation of Pregabalin

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

Renal Impairment

Pregabalin is eliminated from systemic circulation 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 impaired renal function 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 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).

* 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 additional single dose.

Hepatic impairment

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

Geriatric patients

Dose reduction of pregabalin may be required in elderly patients due to impaired renal function (see section "Pharmacokinetics").

Children

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

Overdose

The most commonly reported adverse reactions in pregabalin overdose were somnolence, confusion, agitation, and restlessness. Cases of seizures have also been reported.

Rare cases of coma have been reported.

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

Adverse Reactions

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

The adverse reactions listed below occurred 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 category, 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 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, difficulty in word finding, pathological dreaming, 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: convulsions, parosmia, hypokinesia, dysphagia, parkinsonism, hypalgesia, dependence, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain-Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders.

Eye disorders

Common: blurred vision, diplopia, conjunctivitis.

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

Rare: vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcer, 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 ulcer, 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 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, fall, feeling drunk, unusual sensations, fatigue.

Uncommon: generalized edema, facial swelling, chest tightness, pain, warmth, thirst, chills, general weakness, malaise, abscess, lipodermatosclerosis, 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).

Following discontinuation of short-term or long-term pregabalin therapy, withdrawal symptoms have been observed. Reported symptoms include: insomnia, headache, nausea, anxiety, diarrhea, influenza-like syndrome, convulsions, 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 in paediatric patients with partial seizures with or without secondary generalization was similar to that observed in adult patients with epilepsy. The most commonly reported adverse reactions were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis (see sections "Pharmacodynamics", "Pharmacokinetics" and "Paediatric population").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report any 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 the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

14 capsules in a blister. 2 or 4 blisters in a cardboard package.

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.