Zonik

INSTRUCTION for medical use of the medicinal product ZONIK (ZONIK®)

Composition:

Active substance: pregabalin;

1 ml of solution contains pregabalin 20 mg;

Excipients: sucralose, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), sodium dihydrogen phosphate anhydrous, disodium hydrogen phosphate anhydrous, flavouring additive "Cherry", purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, colourless solution.

Pharmacotherapeutic group. Nervous system. Analgesics. Other analgesics and antipyretics. Gabapentinoids. Pregabalin. ATC code N02BF02.

Pharmacological properties.

Pharmacodynamics.

The active substance, pregabalin, is a gamma-aminobutyric acid analogue [(S)-3-(aminomethyl)-5-methylhexanoic acid].

Mechanism of action

Pregabalin binds to the auxiliary subunit (α2–δ protein) of voltage-dependent calcium channels in the central nervous system (CNS).

Clinical efficacy and safety

Neuropathic pain

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

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

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

In controlled clinical trials of peripheral neuropathic pain, a 50% improvement on the pain rating scale was observed in 35% of patients receiving pregabalin and in 18% of patients receiving placebo. Among patients who did not experience somnolence, such improvement was observed in 33% of patients 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 of central neuropathic pain, a 50% improvement on the pain rating scale was observed in 22% of patients receiving pregabalin and in 7% of patients receiving placebo.

Epilepsy

Adjunctive therapy

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

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

Children

The efficacy and safety of pregabalin as adjunctive therapy in epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study involving patients aged 3 months to 16 years (n = 65) with partial seizures were similar to those in adults. Results from a 12-week placebo-controlled trial involving 295 children aged 4 to 16 years and a 14-day placebo-controlled trial involving 175 children aged 1 month to 4 years, designed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and from two open-label safety trials of 1 year's duration involving 54 and 431 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 "Pharmacological properties", "Dosage and administration", and "Adverse reactions").

In the 12-week placebo-controlled trial, children (aged 4 to 16 years) received pregabalin at 2.5 mg/kg/day (maximum 150 mg/day), pregabalin at 10 mg/kg/day (maximum 600 mg/day), or placebo. The percentage of patients with a reduction in partial seizures of at least 50% from baseline was 40.6% in the group receiving pregabalin at 10 mg/kg/day (p = 0.0068 vs placebo), 29.1% in the group receiving pregabalin at 2.5 mg/kg/day (p = 0.2600 vs placebo), and 22.6% in the placebo group.

In the 14-day placebo-controlled trial, children (aged 1 month to 4 years) received pregabalin at 7 mg/kg/day, pregabalin at 14 mg/kg/day, or placebo. The median daily seizure frequency at baseline and at the end of treatment was 4.7 and 3.8, respectively, for pregabalin at 7 mg/kg/day; 5.4 and 1.4 for pregabalin at 14 mg/kg/day; and 2.9 and 2.3 for placebo. Pregabalin at 14 mg/kg/day significantly reduced the logarithmically transformed frequency of partial seizures compared to placebo (p = 0.0223), while pregabalin at 7 mg/kg/day did not demonstrate improvement compared to placebo.

In a 12-week placebo-controlled trial, 219 patients with primary generalized tonic-clonic seizures (aged 5 to 65 years, of whom 66 were aged 5 to 16 years) received pregabalin at 5 mg/kg/day (maximum 300 mg/day), 10 mg/kg/day (maximum 600 mg/day), or placebo as adjunctive therapy. The percentage of patients with at least a 50% reduction in primary generalized tonic-clonic seizure frequency was 41.3%, 38.9%, and 41.7% for pregabalin 5 mg/kg/day, pregabalin 10 mg/kg/day, and placebo, respectively.

Monotherapy (in patients with newly diagnosed disease)

Pregabalin was studied in one controlled clinical trial of 56 weeks' duration with a dosing regimen of twice daily. When pregabalin was used, equivalent efficacy compared to lamotrigine was not achieved, based on assessment at 6 months using the primary endpoint of seizure freedom. Pregabalin and lamotrigine were equally safe and well tolerated.

Generalized anxiety disorder

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

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

In controlled clinical trials (4–8 weeks' duration), a ≥50% improvement in the 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 was more frequently observed in patients receiving pregabalin than in those receiving placebo. In most cases, this phenomenon resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundus 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. Fundus changes were observed in 1.7% of patients receiving pregabalin and in 2.1% of patients in the placebo group.

Pharmacokinetics.

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

Absorption

Pregabalin is rapidly absorbed after administration on an empty stomach and reaches maximum plasma concentration (Cmax) within 1 hour after single or multiple doses. The calculated oral bioavailability of pregabalin is ≥ 90% and is dose-independent. At steady state, achieved after multiple dosing within 24–48 hours. The absorption rate of pregabalin is reduced when taken with food, resulting in approximately a 25–30% decrease in Cmax and prolongation of the time to reach maximum concentration (tmax) to approximately 2.5 hours. However, administration of pregabalin with food did not have a clinically significant effect on the extent of absorption.

Distribution

Preclinical studies have shown that pregabalin crosses the blood-brain barrier in mice, rats, and monkeys. In rats, pregabalin crosses the placenta and is excreted into milk during lactation. In humans, the volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin does not bind to plasma proteins.

Metabolism

In humans, pregabalin undergoes minimal metabolism. After administration of a radiolabeled dose of pregabalin, approximately 98% of the radioactivity was excreted in urine as unchanged pregabalin. The fraction of the N-methylated 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 "Pharmacological properties", "Renal impairment").

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

Linearity/Non-linearity

The pharmacokinetics of pregabalin are linear over the entire recommended dose range. The variability of pregabalin pharmacokinetics among patients is low (< 20%). Pharmacokinetics after multiple dosing are predictable based on data obtained after single-dose administration. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.

Gender

Clinical trial results indicate the absence of a 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 pregabalin is primarily eliminated by the kidneys, dosage reduction is required for patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Dosage and administration", table).

Hepatic impairment

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is excreted in urine predominantly unchanged, it is unlikely that hepatic impairment would have a significant effect on plasma concentrations of pregabalin.

Children

The pharmacokinetics of pregabalin were evaluated in children with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years, and 12 to 16 years) 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, tmax in plasma was generally similar across all age groups and ranged 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% higher creatinine clearance-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 the apparent volume of distribution of oral pregabalin, and this relationship was similar in children and adult patients.

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

Elderly patients (aged 65 years and older)

Pregabalin clearance tends to decrease with age. This decrease in pregabalin clearance after oral administration is consistent with the age-related decrease in creatinine clearance. Patients with age-related renal impairment may require a reduced dose of pregabalin (see section "Dosage and administration", table).

Lactation period

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

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 negligible metabolism in the human body (≤ 2% of the dose is excreted in urine as metabolites), does not inhibit metabolism of other medicinal products in vitro, and does not bind to plasma proteins, clinically relevant pharmacokinetic interactions between pregabalin and other medicinal products are unlikely, and pregabalin is unlikely to be subject to such 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 has shown that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate have no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and/or ethinylestradiol

Concomitant administration of pregabalin with oral contraceptives, norethisterone and/or ethinylestradiol does not affect the steady-state pharmacokinetics of either agent.

Medicinal products affecting the CNS

Pregabalin may potentiate the effects of ethanol and lorazepam.

During post-marketing surveillance, cases of respiratory depression, coma, and fatal outcomes have been reported in patients who took pregabalin concomitantly with opioids and/or other medicinal products that depress CNS function. Pregabalin is likely to enhance cognitive and gross motor impairment caused by oxycodone.

Interactions in elderly patients

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

Special precautions for use.

Patients with diabetes

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

Hypersensitivity reactions

Post-marketing reports have described the development of 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 (SSARs)

Rare cases of SSARs associated with pregabalin treatment, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. These reactions may be life-threatening or fatal. When prescribing the medicinal product Zonik, 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 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 treated with pregabalin compared to placebo group patients; the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacological properties").

Adverse reactions affecting 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 have been reported, which in some instances were reversible upon discontinuation of pregabalin.

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 monotherapy with pregabalin.

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 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 or 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 these patients (see section "Dosage and administration***"***).

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 antiepileptic drug trials also showed a small increased risk of suicidal thoughts and behavior. The mechanism underlying this risk is unknown. In the post-marketing period, suicidal ideation and behavior have been observed in patients receiving pregabalin (see section "Adverse reactions"). An epidemiological study using a self-controlled design (comparing treatment periods with non-treatment periods within the same individual) demonstrated an increased risk of new-onset suicidal behavior and fatal outcomes due to suicide in patients using pregabalin.

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. Discontinuation of pregabalin therapy should be considered in cases of suicidal ideation or behavior.

Lower gastrointestinal tract dysfunction

Events related to lower gastrointestinal tract dysfunction (intestinal obstruction, paralytic ileus, constipation) have been reported with pregabalin use, particularly when used concomitantly with medications that may cause constipation, such as opioid analgesics. When pregabalin is used with opioids, preventive measures against constipation should be implemented (especially in elderly patients and younger women).

Concomitant use with opioids

Caution is recommended when prescribing pregabalin concomitantly with opioids due to the risk of CNS depression (see section "Interaction with other medicinal products and other forms of interaction"). In a case-control study of opioid users, an increased risk of opioid-related mortality was observed in patients using pregabalin with an opioid compared to those using opioids alone (adjusted odds ratio [aOR], 1.68 [95% confidence interval (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 showed a trend toward higher risk with high-dose pregabalin (> 300 mg, aOR 2.51 [95% CI, 1.24–5.06]).

Misuse, abuse, or dependence

Pregabalin may cause drug dependence, which can 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 should be treated with caution. The risk of misuse, abuse, or dependence should be carefully assessed before initiating pregabalin therapy.

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

Withdrawal symptoms

Withdrawal symptoms have been observed after discontinuation of short-term or long-term pregabalin therapy. Reported symptoms include insomnia, headache, nausea, anxiety, diarrhea, flu-like symptoms, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness. The occurrence of withdrawal symptoms after pregabalin discontinuation may indicate drug dependence (see section "Adverse reactions***"***). This information should be communicated to patients before starting therapy. If pregabalin needs to be discontinued, it is recommended to taper the dose gradually over at least one 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 primarily in patients with concomitant conditions that may predispose to encephalopathy.

Women of childbearing potential / Contraception in women and men

Pregabalin use during the first trimester of pregnancy may cause major congenital malformations (MCMs) in the unborn child. The medicinal product Zonik should not be used during pregnancy except when the expected benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during pregabalin treatment.

Excipients

The product contains methylparaben (E 218) and propylparaben (E 216), which may cause allergic reactions (possibly delayed).

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

Use during 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.

Major congenital malformations

Data from a Scandinavian observational study involving over 2700 pregnant women exposed to pregabalin during the first trimester showed a higher prevalence of major MCMs among live- or stillborn children exposed to pregabalin in utero compared to unexposed children (5.9% vs. 4.1%).

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

An analysis of specific MCMs showed a higher risk for orofacial clefts and defects of the eyes, 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 (only when the expected benefit to the mother clearly outweighs the potential risk to the fetus).

Breastfeeding period

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 benefit of breastfeeding for the child and the benefit of treatment for the woman.

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, 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 observed. The clinical relevance of these findings is unknown.

Effects on ability to drive and use machines.

The medicinal product Zonik may have a slight or moderate influence on the ability to drive and use machines. It may cause dizziness and somnolence, which may affect the ability to drive and operate machinery. Therefore, patients should be advised to refrain from driving, operating complex machinery, and other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform such activities.

Administration and Dosage

Administer independently of food intake.

This medicinal product is intended for oral use only. To ensure accurate dosing, the package contains a dosing syringe.

Doses

The dosage range of the medicinal product may vary between 150–600 mg (7.5–30 mL) 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 (7.5 mL) per day, divided into 2 or 3 doses. Depending on individual response and tolerability, the dose may be increased to 300 mg (15 mL) per day after 3–7 days, and if necessary, to the maximum dose of 600 mg (30 mL) per day after an additional 7 days.

Epilepsy

Treatment with pregabalin may be initiated at a dose of 150 mg (7.5 mL) per day, divided into 2 or 3 doses. Depending on individual response and tolerability, the dose may be increased to 300 mg (15 mL) per day after the first week of treatment. After another week, the dose may be increased to the maximum of 600 mg (30 mL) per day.

Generalized anxiety disorder

The dose, divided into 2 or 3 administrations, may range between 150–600 mg (7.5–30 mL) per day. The need for continued therapy should be periodically reviewed.

Treatment with pregabalin may be initiated at a dose of 150 mg (7.5 mL) per day. Depending on individual response and tolerability, the dose may be increased to 300 mg (15 mL) per day after the first week of treatment. After another week of administration, the dose may be increased to 450 mg (22.5 mL) per day. After an additional week, the dose may be increased to the maximum of 600 mg (30 mL) per day.

Discontinuation of pregabalin

According to current clinical practice, pregabalin therapy should be discontinued gradually over at least one week, regardless of the indication (see sections "Special precautions" 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 "Pharmacological properties"), dosage adjustment in patients with renal impairment should be individualized as indicated in the table below, based on creatinine clearance (CLcr), calculated using the following formula:

Pregabalin is effectively removed from blood plasma by hemodialysis (50% of the drug over 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 medicinal product should be administered immediately after each 4-hour hemodialysis session (see table).

Dosage adjustment of pregabalin according to renal function

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

+Supplemental dose is an additional single dose.

Patients with hepatic impairment

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

Geriatric patients

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

Method of administration of oral solution

Dosing is performed using the oral dosing syringe supplied in the package.

Children.

The safety and efficacy of pregabalin in children under 18 years of age have not been established. Available information is presented in the sections "Side Effects" and "Pharmacological Properties"; however, based on this information, no dosage recommendations can be provided for this patient population.

Overdose.

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

Coma has been reported rarely.

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

Adverse Reactions

In the clinical development program for pregabalin, over 8,900 patients received the drug, including 5,600 participants in double-blind, placebo-controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally mild to moderate in severity. In all controlled trials, the discontinuation rate due to adverse reactions was 12% among patients receiving pregabalin and 5% among those receiving placebo. The most common adverse reactions leading to drug discontinuation in the pregabalin group were dizziness and somnolence.

Below are all adverse reactions occurring more frequently than with placebo and in more than one patient. These adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from 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 reactions such as somnolence (see section "Special Warnings and Precautions for Use").

Additional adverse reactions reported after market authorization of pregabalin are listed below and indicated in italics.

Infections and infestations

Common: nasopharyngitis.

Blood and lymphatic system disorders

Uncommon: neutropenia.

Immune system disorders

Uncommon: hypersensitivity.

Rare: angioedema, allergic reactions, anaphylactoid reactions.

Metabolism and nutrition disorders

Common: increased appetite.

Uncommon: loss of appetite, hypoglycemia.

Psychiatric disorders

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

Uncommon: hallucinations, panic attacks, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood changes, depersonalization, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition, suicidal ideation, suicidal behavior (see section "Special Warnings and Precautions for Use").

Frequency not known: drug dependence.

Nervous system disorders

Very common: dizziness, somnolence, headache.

Common: ataxia, coordination impairment, 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 dysfunction, mental disorder, speech disorders, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, apathy, perioral paresthesia, myoclonus.

Rare: seizures, parosmia, hypokinesia, dysphagia, parkinsonism, hypalgesia, dependence, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal disorder, 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, 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: QT interval prolongation, sinus tachycardia, sinus arrhythmia.

Vascular disorders

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

Respiratory, thoracic and mediastinal disorders

Common: pharyngolaryngeal pain.

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

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

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 bleeding.

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

Hepatobiliary disorders

Uncommon: increased liver enzyme levels (alanine aminotransferase and aspartate aminotransferase).

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, 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 spasms, arthralgia, back pain, limb pain, neck muscle spasms.

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

Rare: rhabdomyolysis.

Renal and urinary disorders

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

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

Reproductive system and breast disorders

Common: erectile dysfunction, impotence.

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

Rare: amenorrhea, galactorrhea, breast enlargement, gynecomastia, cervicitis, balanitis, epididymitis.

General disorders and administration site conditions

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

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

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, suicidal thoughts, pain, hyperhidrosis, and dizziness. These symptoms may indicate drug dependence. This information should be communicated to patients 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 "Special Warnings and Precautions for Use" and "Dosage and Administration").

Children

The safety profile of pregabalin established in five studies involving pediatric patients with partial seizures with or without secondary generalization (a 12-week efficacy and safety study in patients aged 4 to 16 years, n = 295; a 14-day efficacy and safety study in patients aged 1 month to less than 4 years, n = 175; a pharmacokinetic and tolerability study, n = 65; and two open-label, one-year safety studies, n = 54 and n = 431) was similar to that observed in adult epilepsy studies. The most common adverse reactions observed in the 12-week pregabalin treatment study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis. The most common adverse reactions observed in the 14-day pregabalin treatment study were somnolence, upper respiratory tract infections, and pyrexia (see sections "Pharmacological Properties" and "Dosage and Administration").

Reporting of suspected adverse reactions

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

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging.

100 ml in a dark glass bottle with a tamper-evident cap. Each bottle is packaged in a cardboard box with a 5 ml dosing syringe and a syringe adapter.

100 ml in a dark glass bottle with a child-resistant cap. Each bottle is packaged in a cardboard box with a 5 ml dosing syringe and a syringe adapter.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer’s address and location of business operations.

40020, Ukraine, Sumy region, Sumy, Skryabina Street, 54.