Gabana

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GABANA® (GABANA)

Composition:

Active substance: pregabalin;

1 capsule contains 25 mg, 50 mg, 75 mg, 150 mg, or 300 mg of pregabalin calculated as dry substance;

Excipients: lactose monohydrate; pregelatinized starch; talc;

Capsule shell: gelatin, titanium dioxide (E 171), patent blue (E 133) – for 25 mg and 50 mg strengths; gelatin, titanium dioxide (E 171) – for 75 mg strength;

gelatin, titanium dioxide (E 171), Ponceau 4R (E 124), patent blue (E 131), brilliant black (E 151) – for 150 mg strength;

gelatin, Candurin Silver (potassium aluminosilicate E 555, titanium dioxide E 171), brilliant blue (E 133) – for 300 mg strength.

Dosage form. Capsules.

Main physicochemical characteristics:

• 25 mg capsules: hard gelatin capsules size “2” with white body and blue cap; capsule contents – white or almost white powder;
• 50 mg capsules: hard gelatin capsules size “2” with blue body and blue cap; capsule contents – white or almost white powder;
• 75 mg capsules: hard gelatin capsules with white opaque body and white cap; capsule contents – white or almost white powder;
• 150 mg capsules: hard gelatin capsules with white opaque body and blue cap; capsule contents – white or almost white powder;
• 300 mg capsules: hard gelatin capsules size “0” with pearly-blue body and pearly-blue cap; capsule contents – white or almost white powder.

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

Pharmacological Properties

Pharmacodynamics

Active substance – pregabalin, which 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

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

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

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

In controlled clinical trials studying peripheral neuropathic pain, 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 in 18% of placebo group patients. 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 studying centrally mediated neuropathic pain, 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 twice-daily or three-times-daily dosing regimens. Overall, safety and efficacy profiles for twice-daily and three-times-daily dosing 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 including 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, as well as two 1-year open-label safety studies 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. At least a 50% reduction 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. Median daily seizure frequency at baseline and at the end of the visit was 4.7 and 3.8, respectively, in the group receiving pregabalin at 7 mg/kg/day, 5.4 and 1.4 in the group receiving pregabalin at 14 mg/kg/day, and 2.9 and 2.3 in the placebo group. 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 of patients with primary generalized tonic-clonic (PGTC) seizures, 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. At least a 50% reduction in PGTC seizure frequency 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. When pregabalin was used, equivalent efficacy compared to lamotrigine was not achieved, based on the 6-month endpoint assessment – seizure freedom. 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 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 week 1.

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 occurred more frequently 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 within 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 detected in 12.4% of patients receiving pregabalin and in 11.7% of patients in the placebo group. Fundus changes were detected 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 and one 6-week randomized withdrawal trial. These trials included patients diagnosed with fibromyalgia based on American College of Rheumatology criteria (widespread pain for at least 3 months and pain present in 11 or more of 18 specific tender points). The trials demonstrated reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global impression and fibromyalgia impact questionnaire.

Children. A 15-week placebo-controlled trial was conducted involving 107 children aged 12–17 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 common adverse reactions observed in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics

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

Absorption

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

Distribution

Preclinical studies have shown that pregabalin crosses the blood-brain barrier in rats, mice, and monkeys. Pregabalin also crosses the placenta in rats and is excreted into the milk of lactating rats. In humans, the apparent 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 of the medicinal product—detected in urine accounted for 0.9% of the administered dose. During preclinical studies, no racemization of the S-enantiomer of pregabalin to the R-enantiomer occurred.

Elimination

Pregabalin is eliminated from systemic circulation unchanged, primarily by renal excretion. 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 in patients is low (less than 20%). The pharmacokinetics of multiple doses are predictable based on data obtained after single-dose administration. Therefore, there is no need for routine monitoring of pregabalin plasma concentrations.

Gender

Clinical trial results indicate no clinically significant effect of gender on pregabalin plasma concentrations.

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 renal excretion is the main route of elimination of pregabalin, dose reduction is required for patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Dosage and administration", Table 1).

Hepatic impairment

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

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% 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.

Population pharmacokinetic analysis showed that 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 decrease in pregabalin clearance with oral administration is consistent with the age-related decrease in creatinine clearance. Elderly patients with age-related renal impairment may require dose reduction of pregabalin (see section "Dosage and administration", Table 1).

Lactation

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 a negligible effect on the pharmacokinetics of pregabalin. Pregabalin passed into breast milk, with average steady-state concentrations approximately 76% of maternal plasma concentrations. The calculated infant dose received via breast milk (with average milk intake of 150 mL/kg/day) from a mother taking pregabalin at a dose of 300 mg/day or the maximum dose of 600 mg/day was 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the total daily maternal dose normalized to mg/kg.

Clinical characteristics

Indications

Neuropathic pain

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

Epilepsy

Gabana**®** is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalization.

Generalized anxiety disorder

Gabana**®** is indicated for the treatment of generalized anxiety disorder in adults.

Fibromyalgia

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Composition").

Interaction with other medicinal products and other forms of interaction

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

In vivo studies and population pharmacokinetic analysis

In in vivo studies, no clinically significant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol. Population pharmacokinetic analysis showed that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate 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 taking pregabalin concomitantly with opioids and/or other CNS depressants. Pregabalin is likely to enhance cognitive and basic motor function impairment caused by oxycodone.

Interaction in elderly patients

No specific pharmacodynamic interaction studies have been conducted in elderly patients. 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 treatment may require adjustment of their antidiabetic medication doses.

Hypersensitivity reactions

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

Serious skin adverse reactions (SSARs)

Serious skin adverse reactions (SSARs), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which may be life-threatening or fatal, have been rarely reported in association with pregabalin treatment. When prescribing the medicinal product, patients should be informed about the signs and symptoms and closely monitored for skin reactions. If signs or symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative treatment considered (if necessary).

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

Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of traumatic events (falls) in elderly patients. Loss of consciousness, confusion, and psychiatric disturbances have been reported. Therefore, patients should exercise caution until they are aware of the potential effects of the medicinal product.

Visual disorders

During clinical trials, blurred vision was reported more frequently in patients receiving pregabalin compared to those receiving placebo. In most cases, this phenomenon resolved with continued treatment.

Ophthalmological examinations in clinical studies have shown a higher incidence of decreased visual acuity and visual field changes in patients receiving pregabalin compared to placebo group patients; however, the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacological properties. 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. Discontinuation of pregabalin may lead to resolution or reduction of these ocular symptoms.

Renal impairment

Cases of renal impairment have been reported. This effect was sometimes reversible after discontinuation of pregabalin.

Discontinuation of concomitant antiepileptic drugs

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

Withdrawal symptoms

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

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

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

Heart failure

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

Treatment of central neuropathic pain due to spinal cord injury

When treating central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly CNS-related adverse reactions such as somnolence, was increased. This may be related to additive effects of concomitant medications (e.g., antispastic agents) required for treatment of this condition. This should be taken into account when prescribing pregabalin to such patients.

Respiratory depression

Cases of severe respiratory depression have been reported in association with pregabalin use. Patients with impaired respiratory function, respiratory or neurological disorders, renal impairment, patients concurrently taking 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 "Posology and method of administration").

Suicidal thoughts and behaviour

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

Patients (and caregivers) should seek medical help if signs of suicidal thoughts or behaviour occur. Patients should be monitored for emergence of suicidal thoughts and behaviour, and appropriate treatment should be considered. Discontinuation of pregabalin treatment should be considered if suicidal thoughts or behaviour occur.

Worsening of lower gastrointestinal tract function

Events related to worsening of lower gastrointestinal tract function (such as intestinal obstruction, paralytic ileus, constipation) have been reported with pregabalin use, particularly when co-administered with medicinal products that may cause constipation, such as opioid analgesics. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be taken (especially in women and elderly patients).

Concomitant use with opioids

Pregabalin should be used with caution when co-administered with opioids due to the risk of CNS depression (see section "Interaction with other medicinal products and other forms of interaction"). In controlled clinical trials, patients taking pregabalin concomitantly with an opioid had an increased risk of opioid-related fatal outcomes compared to those taking 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 increased risk at higher pregabalin doses (> 300 mg, aOR 2.55 [95% CI, 1.24–5.06]).

Medication misuse, abuse or dependence

Pregabalin may cause drug dependence, which may occur even at therapeutic doses. Cases of misuse and abuse have been reported. Patients with a history of substance abuse may be at higher risk of pregabalin misuse, abuse and dependence; therefore, pregabalin should be used with caution in such patients. Prior to prescribing pregabalin, the risk of misuse, abuse or dependence should be carefully assessed.

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

Encephalopathy

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

Women of childbearing potential/contraception

Pregabalin use during the first trimester of pregnancy may cause major congenital malformations in the fetus. Pregabalin should not be used during pregnancy unless the 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

The medicinal product Gabana**®** contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Gabana**®** 150 mg contains the colourants diamond black and Ponceau 4R (cochineal red 4R), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Women of childbearing potential/contraception for women

Women of childbearing potential should use effective contraception during treatment (see section "Special precautions for use").

Pregnancy

Reproductive toxicity has been demonstrated in animal studies: pregabalin crosses the placenta in rats (see section "Pharmacokinetics"). Pregabalin may cross the human placenta.

Major congenital malformations

In an observational study conducted in Scandinavian countries, involving over 2700 pregnancies, a higher prevalence of major congenital malformations (MCMs) was demonstrated in the paediatric population (live-born or stillborn children) exposed to pregabalin during the first trimester compared to the unexposed population (5.9% vs. 4.1%).

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

Analysis of specific malformations showed a higher risk of malformations of the nervous system, eyes, orofacial clefts, urinary tract and genital organs, but the number of such malformations was small and estimates imprecise.

Gabana**®** should not be used during pregnancy unless clearly necessary (prescribed only when benefit to the mother clearly outweighs the potential risk to the fetus).

Breastfeeding

A small amount of pregabalin has been detected in breast milk of lactating women. Women who are breastfeeding should be advised that breastfeeding is not recommended during pregabalin treatment.

Fertility

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

In a clinical study evaluating the effect of pregabalin on sperm motility in healthy male volunteers, pregabalin was administered at a dose of 600 mg/day. After 3 months of treatment, no effect on sperm motility was observed.

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

Ability to affect reaction speed when driving or operating machinery

Pregabalin may have a slight or moderate influence on the ability to drive or operate machinery. Pregabalin may cause dizziness and somnolence, which may affect the ability to drive or operate machinery. Therefore, patients should be advised to refrain from driving or operating complex machinery or engaging in other potentially hazardous activities until it is known whether pregabalin affects their ability to perform such activities.

Method of Administration and Dosage

Method of Administration

Gabana® should be taken independently of food intake.

Gabana® is intended exclusively for oral administration.

Dosage

The dosage range may vary between 150–600 mg per day. The daily dose should be divided into 2 or 3 doses.

Neuropathic Pain

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the drug's efficacy and patient tolerability, the dose may be increased to 300 mg per day after an interval of 3 to 7 days, and if necessary, to the maximum dose of 600 mg per day after an additional 7-day interval.

Epilepsy

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the drug's efficacy and patient tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week, the dose may be increased to the maximum of 600 mg per day.

Generalized Anxiety Disorder

The dose, divided into 2 or 3 administrations, may be adjusted within the range of 150–600 mg per day. The need for continued treatment should be periodically reassessed.

Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on the drug's efficacy and patient tolerability, the dose may be increased to 300 mg per day after the first week. After another week of treatment, the dose may be increased to 450 mg per day. After an additional week, the dose may be increased to the maximum of 600 mg per day.

Fibromyalgia

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

Discontinuation of Pregabalin Therapy

According to current clinical practice, if pregabalin therapy needs to be discontinued, it is recommended to do so gradually over a period of at least one week, regardless of the indication (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects").

Patients with Renal Impairment

Pregabalin is eliminated from systemic circulation in unchanged form primarily via renal excretion. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage reduction in patients with impaired renal function should be individualized according to creatinine clearance (CLcr), as indicated in Table 1 and calculated using the following formula:

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

Table 1

Dosage Adjustment of Pregabalin According to Renal Function

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

• Additional dose – a single additional dose of the medicinal product.

Patients with hepatic impairment

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

Elderly patients (aged 65 years and older)

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

Children

The safety and efficacy of Gabana**®** in children under 18 years of age have not been established. Available information is presented in the section "Adverse reactions" as well as in sections "Pharmacodynamics" and "Pharmacokin游戏副本", however, based on this information, no dosing recommendations can be provided for this patient population.

Overdose

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

Management of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis (see section "Directions for use and dosage", Table 1).

Adverse Reactions

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

Table 2 lists all adverse reactions that occurred more frequently than with placebo and in more than one patient. These adverse reactions are categorized by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated based on available data).

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 resulting from spinal cord injury, the overall frequency of adverse reactions increased, particularly those affecting the central nervous system (CNS), and especially somnolence (see section "Special Warnings and Precautions for Use").

Additional adverse reactions reported after pregabalin was marketed are included in the list below and are designated under the category "Frequency not known."

Table 2

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

Symptoms of withdrawal have been observed in some patients after discontinuation of short-term or long-term treatment with pregabalin. Reported symptoms included insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, seizures, restlessness, depression, suicidal thoughts, pain, hyperhidrosis, and dizziness, which indicate drug dependence. This information should be communicated to the patient prior to initiating treatment.

Data on pregabalin discontinuation after prolonged 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; two open-label safety studies of 1-year duration, n = 54 and n = 431), was similar to the profile observed in studies in adult patients with epilepsy. The most commonly reported adverse reactions observed 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 observed 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 is of great importance. It allows 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 all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

For 75 mg, 150 mg, 300 mg – 3 years.

For 25 mg, 50 mg – 1 year.

Storage conditions

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

Keep out of reach of children.

Packaging

10 capsules per blister, 2 blisters per carton.

Prescription status

Prescription only.

Manufacturer

JSC "Kyivmedpreparat" – for 25 mg, 50 mg, 75 mg, 150 mg, 300 mg.

LLC "MARIFARM" – for 75 mg, 150 mg, 300 mg.

Manufacturer's address and location of manufacturing site

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.

8 Minarikova Street, Maribor, 2000, Slovenia.