Pregabalin-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Pregabalin-Darnitsa

Composition:

Active ingredient: pregabalin;

1 ml of solution contains 20 mg of pregabalin;

Excipients: methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), sodium dihydrogen phosphate dihydrate, disodium phosphate, sucralose, strawberry flavoring, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs. Pregabalin. ATC code N03A X16.

Pharmacological Properties

Pharmacodynamics

The active substance, pregabalin, is a gamma-aminobutyric acid (GABA) 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 lasting up to 13 weeks with a dosing regimen of twice daily, and in trials lasting up to 8 weeks with a dosing regimen of three times daily. Overall, the safety and efficacy profiles for the twice-daily and three-times-daily regimens were similar.

In clinical trials lasting up to 12 weeks, in which the drug was used for the treatment of neuropathic pain, reduction in peripheral and central 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 lasting 12 weeks with dosing regimens of twice daily or three times daily. Overall, the safety and efficacy profiles for the twice-daily and three-times-daily regimens were similar.

A reduction in seizure frequency was observed as early as the first week.

Children. The efficacy and safety of pregabalin as adjunctive therapy in epilepsy have not been established in children under 12 years of age and adolescents. Adverse reactions observed in a pharmacokinetic and tolerability study that included 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, as well as two open-label safety trials lasting 1 year 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 "Pharmacokinetics", "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 at least a 50% reduction in partial seizures 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 the study visit 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 seizures 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 lasting 56 weeks with a twice-daily dosing regimen. When pregabalin was used, equivalent efficacy compared to lamotrigine was not achieved, based on the 6-month endpoint assessment—seizure-free status. Pregabalin and lamotrigine were equally safe and well tolerated.

Generalized anxiety disorder

Pregabalin was studied in six controlled trials lasting 4–6 weeks, one 8-week trial 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 (lasting 4–8 weeks), improvement of at least 50% 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 observed more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this effect resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundoscopic examination with dilated pupils) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity worsened in 6.5% of patients in the pregabalin group and in 4.8% of patients in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and in 11.7% of patients in the placebo group. Fundoscopic changes were observed in 1.7% of patients receiving pregabalin and in 2.1% of patients in the placebo group.

Fibromyalgia

The efficacy of pregabalin was established in one 14-week double-blind, placebo-controlled, multicenter trial (F1) and one 6-week randomized withdrawal trial (F2). Patients enrolled in these trials had a diagnosis of fibromyalgia based on American College of Rheumatology criteria (widespread pain lasting at least 3 months and pain present in 11 or more of 18 specific tender points). The trials demonstrated a reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global assessment and fibromyalgia impact questionnaire.

Children. A 15-week placebo-controlled trial was conducted in 107 children aged 12 to 17 years with fibromyalgia who received pregabalin at doses of 75–450 mg/day. Based on the assessment of the primary efficacy endpoint (change in overall pain intensity from baseline to week 15; measured using an 11-point rating scale), numerically greater improvement was observed in patients receiving pregabalin compared to those receiving placebo, but this improvement did not reach statistical significance. 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 administration on an empty stomach and reaches maximum plasma concentration (Cmax) within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥ 90% and is dose-independent. At steady state, achieved after 24–48 hours of multiple dosing. The rate of pregabalin absorption is reduced when taken with food, resulting in approximately a 25–30% decrease in Cmax and prolongation of time to 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 "Pharmacokinetics. Renal impairment").

Dose 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 from single-dose administration. Therefore, there is no need for routine monitoring of pregabalin plasma concentrations.

Gender

Clinical trial data 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 pregabalin is primarily eliminated by the kidneys, dose 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, hepatic impairment is unlikely to 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, 5, 10, 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, ranging from 0.5 to 2 hours after administration.

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

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

In 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.

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

Elderly patients (aged 65 years and older)

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

Lactation period

The pharmacokinetics of pregabalin administered at a dose 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 minimal effect on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk, with an average steady-state concentration of approximately 76% of the maternal plasma concentration. The calculated dose received by the infant through 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/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

Treatment of peripheral or central neuropathic pain in adults.

Epilepsy

Adjunctive therapy for partial seizures with or without secondary generalization in adults.

Generalized anxiety disorder

Treatment of generalized anxiety disorder in adults.

Fibromyalgia

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

Since pregabalin is predominantly excreted unchanged in urine, undergoes negligible metabolism in humans (≤ 2% of the dose is excreted in urine as metabolites), does not inhibit the metabolism of other medicinal products in vitro, and does not bind to plasma proteins, it is unlikely that pregabalin would cause or be subject to pharmacokinetic interactions.

In vivo studies and population pharmacokinetic analysis

Thus, in in vivo studies, no clinically significant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol. Population pharmacokinetic analysis demonstrated that oral antidiabetic 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 the post-marketing surveillance period, cases of respiratory depression, coma, and fatal outcomes have been reported in patients who received pregabalin concomitantly with opioids and/or other centrally acting medicinal products. Pregabalin is likely to enhance cognitive and gross motor function impairment caused by oxycodone.

Interactions in elderly patients (aged 65 years and older)

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 patients with diabetes whose body weight has increased during pregabalin therapy may require adjustment of antidiabetic medication doses.

Hypersensitivity reactions

Following the marketing of pregabalin, hypersensitivity reactions including angioedema have been reported. If symptoms of angioedema such as facial swelling, perioral swelling, or swelling of the upper airways occur, pregabalin should be discontinued immediately.

Dizziness, somnolence, loss of consciousness, confusion, and psychiatric disturbances

Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of traumatic events (falls) in elderly patients. Additionally, post-marketing reports have included 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 those in the placebo group; however, the incidence of fundus changes was higher in the placebo group (see section "Pharmacodynamics").

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, sometimes reversible upon discontinuation of pregabalin, have been reported.

Severe skin adverse reactions (SSARs)

Rare cases of severe skin adverse reactions associated with pregabalin treatment, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which may be life-threatening or fatal, have been reported. When prescribing Pregabalin-Darnitsya, patients should be informed about the signs and symptoms of these reactions, 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).

Discontinuation of concomitant antiepileptic drugs

There is insufficient data on whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved by adding pregabalin to the treatment regimen, to switch to pregabalin monotherapy.

Withdrawal symptoms

Withdrawal symptoms have been observed in some patients after discontinuation of short-term or long-term pregabalin therapy. Reported events include insomnia, headache, nausea, anxiety, diarrhea, flu-like symptoms, restlessness, depression, pain, seizures, hyperhidrosis, dizziness, and suicidal thoughts, indicating physical dependence. This information should be communicated to patients prior to initiating therapy.

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

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

Heart failure

Cases of 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 (CNS), such as somnolence, increased. This may be related to the additive effect 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 adjustment may be required in 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. Meta-analysis of data from randomized, placebo-controlled antiepileptic drug trials also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude the possibility of increased risk with pregabalin use.

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

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. Preventive measures for constipation should be taken when pregabalin is used with opioids (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% 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]).

Abuse, misuse, or dependence

Cases of abuse, misuse, and dependence have been reported. The medicinal product should be used with caution in patients with a history of substance abuse, and patients should be monitored for symptoms of pregabalin abuse, misuse, or dependence (cases of addiction, dose escalation, and drug-seeking behavior have been reported).

Encephalopathy

Cases of encephalopathy have been reported, occurring predominantly in patients with comorbid conditions that may predispose to encephalopathy.

Women of reproductive age/contraception for women and men

Pregabalin use during the first trimester of pregnancy may cause serious congenital malformations (CMs) in the unborn child. Pregabalin-Darnitsya should not be used during pregnancy except when the benefit to the mother clearly outweighs the potential risk to the fetus. Women of reproductive age should use effective contraception during pregabalin treatment.

Important information on excipients

The medicinal product contains methyl parahydroxybenzoate (E 218) and propyl parahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed).

This medicinal product contains a small amount (less than 100 mg/dose) of ethanol, which is part of the flavoring agent.

Use during pregnancy or breastfeeding.

Women of reproductive age/contraception

Women of reproductive age should use effective contraception.

Pregnancy

Reproductive toxicity has been demonstrated in animal studies. Pregabalin has been shown to cross the placenta in rats. Pregabalin may cross the human placenta.

Serious CMs

Data from a Scandinavian observational study involving over 2700 pregnant women exposed to pregabalin in the first trimester showed 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 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% confidence interval: 1.14 (0.96–1.35)), and compared to those 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 of orofacial clefts and defects of the eyes, nervous system, or genitourinary system, although the numbers were small and estimates imprecise.

Pregabalin-Darnitsya should not be used during pregnancy unless clearly necessary (when the 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 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 600 mg/day. After 3 months of treatment, no effect on sperm motility was observed.

In fertility studies in female rats, an adverse effect on reproductive function was observed. In fertility studies in male rats, an adverse effect on reproductive function and development was observed. The clinical significance of these findings is unknown.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product may have a minor or moderate influence on the ability to drive and operate machinery. 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 (from 7.5 mL to 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 per day, divided into 2 or 3 doses. Depending on the 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 another 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 the 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 vary 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 the 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 treatment, 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.

Fibromyalgia

The recommended dose of the medicinal product for the treatment of fibromyalgia is from 300 mg (15 mL) to 450 mg (22.5 mL) per day. Treatment should be initiated with a dose of 75 mg twice daily (3.75 mL each) or 150 mg (7.5 mL) per day. Depending on efficacy and tolerability, the dose may be increased to 150 mg twice daily (7.5 mL each) or 300 mg (15 mL) per day within one week. For patients in whom a dose of 300 mg (15 mL) per day is insufficiently effective, the dose may be increased to 225 mg twice daily (11.25 mL each) or 450 mg (22.5 mL) per day. Although studies have evaluated a dose of 600 mg (30 mL) per day, there is no evidence that this dose provides additional benefit, and it was associated with poorer tolerability. Due to dose-dependent adverse reactions, doses above 450 mg (22.5 mL) per day are not recommended. Since pregabalin is primarily eliminated by the kidneys, dosage adjustment is required in patients with renal impairment.

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 the clearance of pregabalin is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage should be individually adjusted in patients with impaired renal function as indicated in the table below, based on creatinine clearance (CLcr), calculated using the following formula:

Pregabalin is effectively removed from plasma by haemodialysis (50 % of the drug within 4 hours). For patients undergoing haemodial游戏副本

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

• Additional dose means an extra single dose.

Patients with hepatic impairment

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

Elderly patients (aged 65 years and older)

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

Method of administration

1. Open the vial cap and remove the protective cap from the dosing syringe (Fig. 1).
2. Insert the dosing syringe into the adapter, turn the vial upside down, and draw the required volume of the medicinal product (Fig. 2 and 3).
3. Remove the filled syringe from the vial in an upright position (Fig. 4).
4. Place the dosing syringe into the oral cavity, then slowly press the plunger to administer the contents of the syringe (Fig. 5).
5. Repeat steps 2 to 4 as necessary to achieve the required dose.
6. After use, close the vial by screwing the cap back on (the adapter remains in place). Rinse the dosing syringe with water, dry it, and cover it with the protective cap (Fig. 6).

Children

The safety and efficacy of pregabalin in pediatric patients (under 18 years of age) have not been established. Available data are presented in the section "Adverse reactions" as well as in sections "Pharmacodynamics" and "Pharmacokinetics"; however, based on these data, 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. 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 "Method of administration and dosage", table).

Adverse Reactions

In the clinical development program for pregabalin, over 8900 patients received the drug, including 5600 participants in double-blind, placebo-controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally of mild to moderate intensity. In all controlled trials, the discontinuation rate due to adverse reactions was 12% among patients receiving pregabalin and 5% among those receiving placebo. The most common adverse reactions leading to discontinuation of study medication in the pregabalin group were dizziness and somnolence.

Below are listed all adverse reactions occurring more frequently than with placebo and in more than one patient. These adverse reactions are categorized by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 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 group, adverse reactions are listed in decreasing order of 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 frequency of adverse reactions increased, particularly CNS-related adverse reactions such as somnolence (see section "Special Warnings and Precautions for Use").

Additional adverse reactions reported after the marketing of pregabalin are listed below and indicated in italics.

Eye disorders

Common: blurred vision, diplopia, conjunctivitis.

Uncommon: peripheral vision loss, visual disturbance, eye swelling, visual field defects, reduced visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, blepharitis, accommodation disorder, subconjunctival 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.

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, increased salivation, oral hypoaesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, rectal hemorrhage.

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

Hepatobiliary disorders

Uncommon: increased liver enzymes*.

Rare: jaundice.

Very rare: liver failure, hepatitis.

Renal and urinary disorders

Uncommon: urinary incontinence, dysuria, albuminuria, hematuria, nephrolithiasis, nephritis.

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

Metabolism and nutrition disorders

Common: increased appetite.

Uncommon: decreased appetite, hypoglycemia.

Nervous system disorders

Very common: dizziness, somnolence, headache.

Common: ataxia, coordination disorder, tremor, dysarthria, amnesia, memory impairment, attention disturbance, paresthesia, hypoaesthesia, sedation, balance disorder, lethargy.

Uncommon: syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive disorder, mental disturbance, speech disorder, 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.

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, abnormal dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition.

Cardiac disorders

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

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

Vascular disorders

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

Blood and lymphatic system disorders

Uncommon: neutropenia.

Immune system disorders

Uncommon: hypersensitivity.

Rare: angioedema, allergic reactions, anaphylactoid reactions.

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.

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, fall, feeling drunk, unusual feelings, fatigue, asthenia.

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

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

Infections and infestations

Common: nasopharyngitis.

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 alanine aminotransferase and aspartate aminotransferase levels.

In some patients, symptoms of drug withdrawal have been observed after discontinuation of short-term or long-term pregabalin therapy. Reported reactions include insomnia, headache, nausea, anxiety, diarrhea, flu-like symptoms, seizures, restlessness, depression, pain, hyperhidrosis, dizziness, and suicidal ideation, suggesting physical dependence. This information should be communicated to patients prior to initiating therapy.

Data on withdrawal after long-term pregabalin use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.

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, 1-year safety studies, n=54 and n=431) was similar to that observed in adult epilepsy studies. The most commonly observed adverse reactions in the 12-week pregabalin therapy study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis. The most commonly observed adverse reactions in the 14-day pregabalin therapy study were somnolence, upper respiratory tract infections, and pyrexia (see sections "Pharmacodynamics", "Pharmacokinetics", and "Dosage and Administration").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous 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/or lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Shelf life after first opening of the bottle – 30 days.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of reach of children.

Packaging. 200 ml in a bottle with adapter, closed with a tamper-evident cap; 1 bottle with dosing syringe in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and location of operations.

13 Boryspylska Street, Kyiv, 02093, Ukraine.