Pregabalin-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PREGABALIN-ZN (PREGABALIN-ZN)

Composition:

Active substance: pregabalin;

1 ml of oral solution contains 20 mg of pregabalin;

Excipients: methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), sodium dihydrogen phosphate anhydrous (E 339), sodium hydrogen phosphate anhydrous (E 339), sucralose (E 955), strawberry flavouring (containing ethyl acetate and propylene glycol), purified water.

Pharmaceutical form. Oral solution.

Main physico-chemical properties: clear, colourless liquid with a characteristic strawberry odour.

Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs.

ATC code N03AX16.

Pharmacological Properties.

Pharmacodynamics.

The active substance – pregabalin – is a structural analogue of γ-aminobutyric acid with the chemical name (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 the drug has been demonstrated in clinical trials for the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of pregabalin in other types of neuropathic pain has not been studied.

Pregabalin was evaluated 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 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 lasting up to 12 weeks, in which the medicinal product was used for the treatment of neuropathic pain, reduction in pain of both peripheral and central origin 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 receiving pregabalin and 18% of those 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 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 less than 4 years, designed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and two open-label safety trials of 1 year duration involving 54 and 431 children, respectively, 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. A reduction of at least 50% in partial seizures from baseline was observed in 40.6% of patients receiving pregabalin at 10 mg/kg/day (p=0.0068 vs placebo), 29.1% of patients receiving pregabalin at 2.5 mg/kg/day (p=0.2600 vs placebo), and 22.6% of those receiving placebo.

In the 14-day placebo-controlled trial, children (aged 1 month to less than 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 trial 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); pregabalin at 7 mg/kg/day did not demonstrate improvement compared to placebo.

In a 12-week placebo-controlled trial in patients with primary generalized tonic-clonic seizures (PGTCS), 219 patients aged 5 to 65 years (including 66 patients 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. A reduction of at least 50% in primary PGTCS was observed in 41.3%, 38.9%, and 41.7% of patients receiving pregabalin at 5 mg/kg/day, pregabalin at 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. Pregabalin did not achieve comparable efficacy to lamotrigine, as assessed at 6 months using the primary endpoint of seizure-free status. Pregabalin and lamotrigine were similarly safe and well tolerated.

• Generalized anxiety disorder

Pregabalin was studied in six controlled trials lasting 4–6 weeks, one 8-week trial in 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, as measured by the Hamilton Anxiety Rating Scale (HAM-A), was observed as early as week 1.

In controlled clinical trials (lasting 4–8 weeks), 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 receiving placebo.

During controlled trials, blurred vision occurred more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this effect resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundus examination with dilated pupils) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity decreased 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 oral administration on an empty stomach, reaching maximum plasma concentration (Cmax) within 1 hour after single or multiple doses. The estimated bioavailability of pregabalin after oral administration is ≥90% and is dose-independent. At steady state, achieved within 24–48 hours with repeated dosing. The rate of pregabalin absorption 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, co-administration of pregabalin with food does 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. It has been established that pregabalin crosses the placenta in rats and is excreted into the milk of lactating rats. In humans, the volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin does not bind to plasma proteins.

Metabolism

In humans, pregabalin undergoes minimal metabolism. After administration of a radiolabeled dose of pregabalin, approximately 98% of the radioactivity was excreted in urine as unchanged pregabalin. The fraction of the main metabolite, N-methylated derivative of pregabalin, 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 was observed.

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 1).

Linearity/Non-linearity

The pharmacokinetics of pregabalin are linear across the entire recommended dose range. The variability of pregabalin pharmacokinetics among patients is low (<20%). Pharmacokinetics after multiple dosing are predictable based on data from single-dose administration. Therefore, routine monitoring of plasma concentrations of pregabalin is not necessary.

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 concentration of pregabalin decreases by approximately 50%). Since the drug is primarily eliminated by the kidneys, dose reduction is required in patients with renal impairment, and a supplemental dose should be administered after hemodialysis (see section "Dosage and administration", Table 1).

Hepatic impairment

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes negligible metabolism and is excreted predominantly unchanged in urine, 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 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 dose in each age group. 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 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 "Pharmacodynamics", "Dosage and administration", and "Adverse reactions").

Elderly patients

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

Lactation period

The pharmacokinetics of pregabalin after administration 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 the pharmacokinetics of pregabalin. Pregabalin was excreted into breast milk, with mean steady-state concentrations in milk being approximately 76% of maternal plasma concentrations. The calculated infant dose received via breast milk (assuming average milk intake of 150 mL/kg/day) from a woman taking pregabalin at 300 mg/day or at the maximum dose of 600 mg/day was 0.31 mg/kg/day 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.

The medicinal product is indicated for the treatment of peripheral or central neuropathic pain in adults.

Epilepsy.

The medicinal product is indicated for adults as adjunctive therapy for partial seizures with or without secondary generalization.

Generalized anxiety disorder.

The medicinal product is indicated for the treatment of generalized anxiety disorder in adults.

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 interaction.

Pregabalin is eliminated by the kidneys, mainly in unchanged form, and undergoes negligible metabolism in humans (< 2% of the dose is found as metabolites in urine). Pregabalin does not inhibit the metabolism of other medicinal products in vitro and does not bind to plasma proteins; therefore, it is unlikely to cause or participate in pharmacokinetic interactions.

In vivo studies and population pharmacokinetic analysis

In in vivo studies, no clinically significant pharmacokinetic interaction was 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 had no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and/or ethinylestradiol

Concomitant administration of pregabalin and oral contraceptives containing norethisterone and/or ethinylestradiol had no effect on the steady-state pharmacokinetics of either agent.

Medicinal products affecting the CNS

Pregabalin may enhance the effects of ethanol and lorazepam. In the post-marketing surveillance period, cases of respiratory depression, coma, and death have been reported in patients who took pregabalin concomitantly with opioids and/or other medicinal products that depress CNS function. Pregabalin is likely to potentiate the cognitive and gross motor 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 younger adult patients.

Special precautions for use.

Patients with diabetes

According to current clinical practice, certain patients with diabetes who experience weight gain during pregabalin therapy may require adjustment of hypoglycemic drug doses.

Hypersensitivity reactions

Post-marketing studies have reported hypersensitivity reactions, including, in isolated cases, angioedema. If symptoms of angioedema such as facial swelling occur, pregabalin should be discontinued immediately.

Severe skin adverse reactions

Rare cases of severe skin adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with pregabalin treatment, which may be life-threatening or fatal. Patients should be informed of the signs and symptoms and closely monitored for skin reactions during treatment. If signs or symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative therapy considered (if necessary).

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

Pregabalin therapy has been associated with symptoms such as dizziness and somnolence, which may lead to injuries from falls in elderly patients. Post-marketing studies have reported cases of loss of consciousness, confusion, and psychiatric disturbances; therefore, patients should be cautious when using the drug.

Visual disturbances

In controlled clinical trials, the number of patients reporting blurred vision was higher in the pregabalin group than in the placebo group. In most cases, this adverse effect occurred during ongoing therapy. In studies involving ophthalmological examinations, patients receiving pregabalin showed a higher frequency of decreased visual acuity and visual field changes compared to those receiving placebo. Changes in the fundus were more common in the placebo group.

Post-marketing data also include reports of adverse effects on the eye, including vision loss, blurred vision, or other changes in visual acuity, most of which were transient. Discontinuation of pregabalin in such cases may lead to resolution or significant improvement of ocular symptoms.

Renal impairment

Cases of renal impairment have been reported; however, in some cases, this adverse effect was reversible upon discontinuation of pregabalin.

Discontinuation of concomitant antiepileptic therapy

There is insufficient data on discontinuing concomitant antiepileptic drugs after seizure control has been achieved with the addition of pregabalin to support switching to pregabalin monotherapy.

Withdrawal syndrome

After discontinuation of short-term and long-term pregabalin therapy, withdrawal syndrome has been observed in some patients. Symptoms reported include sleep disturbances, headache, nausea, anxiety, diarrhea, flu-like symptoms, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness, indicating physical dependence. Patients should be informed of this prior to initiating therapy.

Seizures (including status epilepticus) and generalized seizures may occur during pregabalin treatment or shortly after 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

Post-marketing data indicate cases of heart failure in some patients treated with pregabalin. These reactions were primarily observed in elderly patients with cardiovascular dysfunction who were treated with pregabalin for neuropathic symptoms. The drug should be used with caution in such patients. This reaction may be reversible upon discontinuation of pregabalin.

Central neuropathic pain due to spinal cord injury

When treating central neuropathic pain resulting from spinal cord injury, the overall frequency of adverse events, particularly CNS-related adverse reactions such as somnolence, was increased. This may be related to the additive effect of concomitant medications, such as muscle relaxants. This should be taken into account when prescribing pregabalin for such conditions.

Respiratory depression

There have been reports of severe respiratory depression associated with pregabalin use. Patients with respiratory dysfunction, respiratory or neurological disorders, renal impairment, those concurrently using CNS depressants, and elderly patients may be at higher risk of this serious adverse reaction. Dose adjustment may be required for these patients (see section "Dosage and administration").

Suicidal thoughts and suicidal behavior

Suicidal thoughts and suicidal behavior have been reported in patients receiving antiepileptic drugs. Meta-analysis of data from randomized, placebo-controlled trials with antiepileptic drugs showed a slightly increased risk of suicidal thoughts and behavior. The mechanism of this adverse reaction is unknown. During the post-marketing period, cases of suicidal thoughts and behavior have been observed in patients treated with pregabalin (see section "Adverse reactions"). An epidemiological study using a self-controlled design (comparing treatment periods with non-treatment periods within individuals) demonstrated an increased risk of new-onset suicidal behavior and suicide death in patients using pregabalin.

Patients (and their caregivers) should be advised to seek medical help if suicidal thoughts or behavior occur. Patients should be closely monitored for signs of suicidal thoughts and behavior, and appropriate treatment should be initiated. Discontinuation of pregabalin therapy should be considered in cases of suicidal thoughts or behavior.

Lower gastrointestinal tract dysfunction

Post-marketing data include reports of lower gastrointestinal tract dysfunction (e.g., intestinal obstruction, colonic pseudo-obstruction, constipation) in patients taking pregabalin concomitantly with drugs known to cause constipation, such as opioid analgesics. When pregabalin is used with opioids, preventive measures against constipation should be taken (especially in female and elderly patients).

Concomitant use with opioids

Concomitant use of pregabalin with opioids is recommended with caution due to the risk of CNS depression (see section "Interaction with other medicinal products and other forms of interaction"). In a case-control study involving opioid users, patients who took pregabalin with an opioid had an increased risk of opioid-related death compared to those using opioids alone (adjusted odds ratio [aOR], 1.68 [95% CI 1.19–2.36]). This increased risk was observed at low pregabalin doses (≤ 300 mg, aOR 1.52 [95% CI 1.04–2.22]), with a trend toward higher risk at high doses (> 300 mg, aOR 2.51 [95% CI 1.24–5.06]).

Use not according to prescription, potential for abuse or dependence

Cases of misuse, abuse, and dependence on pregabalin have been reported. The drug should be used with caution in patients with a history of substance dependence, and patients should be monitored for signs of misuse, abuse, or dependence (reports include drug craving, dose escalation, and substance-dependent behavior).

Encephalopathy

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

Women of childbearing potential/contraception

Use of pregabalin during the first trimester of pregnancy may cause serious congenital malformations in the unborn child. Pregabalin should not be used during pregnancy unless the expected benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment (see section "Use during pregnancy or breastfeeding").

Excipients that may cause allergic reactions

The medicinal product contains methylparahydroxybenzoate (E 218) and propylparahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception

Women of childbearing potential should use effective contraception.

Pregnancy

Reproductive toxicity has been demonstrated in animal studies.

Pregabalin has been shown to cross the placenta in rats (see section "Pharmacokinetics"). Pregabalin may cross the human placenta.

Major congenital malformations (MCM)

Data from a Scandinavian observational study of over 2700 pregnancies exposed to pregabalin in the first trimester showed a higher prevalence of MCM among children (live-born or stillborn) exposed to pregabalin compared to the unexposed population (5.9% vs. 4.1%).

The risk of MCM in the population exposed to pregabalin in the first trimester was slightly higher than in the unexposed population (adjusted prevalence ratio and 95% CI: 1.14 (0.96–1.35)), as well as compared to populations exposed to lamotrigine (1.29 (1.01–1.65)) or duloxetine (1.39 (1.07–1.82)).

Analysis of specific malformations showed higher risks for nervous system malformations, eye malformations, orofacial clefts, genitourinary malformations, and genital organ malformations, but numbers were small and estimates imprecise.

Pregabalin should not be used during pregnancy except in cases of extreme necessity (when the expected benefit to the mother clearly outweighs the potential risk to the fetus).

Lactation period

Pregabalin is excreted in breast milk (see section "Pharmacokinetics"). It is unknown whether pregabalin affects newborns/infants. The need to discontinue breastfeeding or discontinue pregabalin therapy should be considered on a case-by-case basis, taking into account both the benefits of breastfeeding for the infant and the benefits of therapy for the mother.

Fertility

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

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

In fertility studies in female rats, an adverse effect on reproduction was observed. In fertility studies in male rats, adverse effects on reproduction and development were observed. The clinical relevance of these findings is unknown.

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

The drug has a minor or moderate effect on the ability to drive vehicles or operate machinery. It may cause dizziness and somnolence, which may impair the ability to drive or operate machinery. Patients are advised not to drive or operate complex machinery, or engage in any other potentially hazardous activities, until it is known whether this medicinal product affects such activities in an individual case.

Administration and Dosage

Dosing

The daily dose is 150–600 mg (7.5–30 mL), divided into 2–3 doses.

Neuropathic pain

Treatment may be initiated with a daily dose of 150 mg of pregabalin (7.5 mL), divided into 2–3 doses. Depending on the patient's response and individual tolerability, after 3–7 days the daily dose may be increased to 300 mg (15 mL). If necessary, after another 7 days the dose may be increased to the maximum daily dose of 600 mg (30 mL).

Epilepsy

Treatment may be initiated with a daily dose of 150 mg of pregabalin (7.5 mL), divided into 2–3 doses. Depending on the patient's response and individual tolerability, after 1 week the daily dose may be increased to 300 mg (15 mL). If necessary, after another week the dose may be increased to the maximum daily dose of 600 mg (30 mL).

Generalized anxiety disorders

The daily dose is 150–600 mg (7.5–30 mL), divided into 2–3 doses. The need for continued therapy should be regularly reassessed.

Treatment with pregabalin may be initiated at a daily dose of 150 mg (7.5 mL). Depending on the clinical response and individual tolerability, after 1 week the daily dose may be increased to 300 mg (15 mL). After another week, the daily dose may be increased to 450 mg (22.5 mL). After a further week, the daily dose may be increased to the maximum dose of 600 mg (30 mL).

Discontinuation of pregabalin

According to current clinical practice, pregabalin should be discontinued gradually over a minimum of 1 week, regardless of the indication (see sections "Special precautions" and "Adverse reactions").

Renal impairment

Pregabalin is eliminated from systemic circulation unchanged, primarily via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage reduction in patients with renal impairment should be individualized based on creatinine clearance (CLcr). The creatinine clearance values listed in Table 1 are calculated using the following formula:

Pregabalin is effectively removed from blood plasma by hemodialysis (50% of the active substance within 4 hours). In patients undergoing hemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, an additional dose should be administered after each 4-hour hemodialysis procedure (see Table 1).

Table 1

Dosage adjustment of pregabalin according to renal function

*The total daily dose (mg/day) should be divided by the specified number of doses according to the dosing regimen to obtain the mg/dose value.

+The supplemental dose is a single additional dose.

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment (see section "Pharmacokinetics").

Elderly patients

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

Method of administration

The drug can be taken regardless of food intake.

The drug is intended for oral use only.

Children.

The safety and efficacy of the drug in children under 18 years of age have not been established. Available data to date are presented in sections "Pharmacological properties" and "Adverse reactions", but there are no recommendations regarding dosage.

Overdose.

Adverse reactions associated with pregabalin overdose reported during post-marketing surveillance include somnolence, confusion, agitation, and restlessness. Seizures have also been reported.

Coma has been reported rarely.

Management of pregabalin overdose includes general supportive measures, including hemodialysis if necessary (see Table 1).

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 or moderate severity. In all controlled trials, the discontinuation rate due to adverse reactions was 12% among patients receiving pregabalin and 5% among those receiving placebo. The most common adverse reactions leading to discontinuation of study medication in the pregabalin group were dizziness and somnolence.

Table 2 lists all adverse reactions observed more frequently than in patients receiving placebo and occurring in more than one patient.

Adverse reactions are classified by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and 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 medications used together with pregabalin.

In the treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly CNS-related adverse reactions such as somnolence, was increased (see section "Special Warnings and Precautions for Use").

Other adverse reactions identified during post-marketing surveillance are listed in italics.

Table 2

Adverse reactions of pregabalin

*Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

Following discontinuation of short-term and long-term pregabalin therapy, withdrawal syndrome was observed in some patients. The following reactions have been reported: sleep disturbances, headache, nausea, anxiety, diarrhea, flu-like symptoms, seizures, restlessness, depression, suicidal thoughts, pain, hyperhidrosis, and dizziness, indicating physical dependence. Patients should be informed about this prior to initiating therapy.

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

Children and adolescents

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 safety studies lasting 1 year, n = 54 and n = 431) was similar to the profile observed in adult epilepsy studies. The most commonly reported 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 reported 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 of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows for ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Shelf life after opening the bottle – 1 month when stored at a temperature not exceeding 25 °C.

Storage conditions.

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

Keep out of reach of children.

Packaging. 100 ml or 200 ml in a bottle. 1 bottle with a dosing device in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and location of its business activities.

41 Kuilikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine