capsule shell: gelatin, titanium dioxide (E 171), ponso 4R (E 124), patent blue (E 131), diamond black (E 151) – for 150 mg dosage;
Dosage form
Capsules.
Main physicochemical properties:
150 mg capsules: hard gelatin capsules with a white opaque body and a blue cap; capsule contents – white or almost white powder;
Pharmacotherapeutic group
Antiepileptic drugs. ATX code N03A X16.
Pharmacological properties
Pharmacodynamics
The active substance is pregabalin, which is an analogue of gamma-aminobutyric acid [(S)-3-(aminomethyl)-5-methylhexanoic acid].
Mechanism of action.
Pregabalin binds to the auxiliary subunit (a2–d protein) of voltage-gated calcium channels in the central nervous system (CNS).
Clinical efficacy and safety.
Neuropathic pain.
Studies have shown the drug to be effective in treating diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The drug's effectiveness in other types of neuropathic pain has not been studied.
Pregabalin has been studied in 10 controlled clinical trials of up to 13 weeks duration with twice-daily dosing and in trials of up to 8 weeks duration with three times-daily dosing. Overall, the safety and efficacy profiles for the twice-daily and three times-daily dosing regimens were similar.
In clinical studies of up to 12 weeks duration in which the drug was used to treat neuropathic pain, a reduction in peripheral and central pain was observed after the first week and was maintained throughout the treatment period.
In controlled clinical trials of peripheral neuropathic pain, 35% of patients treated with pregabalin and 18% of patients treated with placebo achieved a 50% improvement in pain scores. Among patients who did not experience somnolence, this improvement was observed in 33% of patients treated with pregabalin and 18% of patients treated with placebo. Among patients who experienced somnolence, the proportion of patients who responded to treatment was 48% in the pregabalin group and 16% in the placebo group.
In a controlled clinical trial in central neuropathic pain, 22% of patients treated with pregabalin and 7% of patients treated with placebo had a 50% improvement in pain scores.
Epilepsy.
Adjunctive therapy: Pregabalin has been studied in 3 controlled clinical trials of 12 weeks duration with twice- or three-times-daily dosing regimens. Overall, the safety and efficacy profiles for the twice- and three-times-daily dosing regimens were similar.
A decrease in the frequency of seizures was observed already in the first week.
Children: The efficacy and safety of pregabalin as an 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 in patients aged 3 months to 16 years (n=65) with partial onset seizures were similar to those seen in adults. Results from a 12-week placebo-controlled study in 295 children aged 4 to 16 years to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial onset seizures and a 1-year open-label safety study in 54 children aged 3 months to 16 years with epilepsy indicate that adverse reactions such as pyrexia and upper respiratory tract infections are more common in children than in adult patients with epilepsy (see sections 4.2, 4.8 and 4.8).
In a 12-week placebo-controlled study, children were given pregabalin 2.5 mg/kg/day (maximum 150 mg/day), pregabalin 10 mg/kg/day (maximum 600 mg/day), or placebo. At least a 50% reduction in partial onset seizures from baseline was observed in 40.6% of patients receiving pregabalin 10 mg/kg/day (p=0.0068 vs. placebo), 29.1% of patients receiving pregabalin 2.5 mg/kg/day (p=0.2600 vs. placebo), and 22.6% of those receiving placebo.
Monotherapy (in newly diagnosed patients). Pregabalin was studied in 1 controlled clinical trial of 56 weeks duration with twice daily dosing. Pregabalin was not non-inferior to lamotrigine as assessed at 6 months for the seizure-free endpoint. Pregabalin and lamotrigine were equally safe and well tolerated.
Generalized anxiety disorder.
A reduction in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Assessment Scale (HAM-A) was observed as early as 1 week.
In controlled clinical trials (4-8 weeks duration), 52% of patients treated with pregabalin and 38% of patients treated with placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.
In controlled trials, blurred vision was more frequently observed in patients treated with pregabalin than in patients treated with placebo. In most cases, this phenomenon resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and dilated fundus examination) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity deteriorated in 6.5% of patients in the pregabalin group and 4.8% of patients in the placebo group. Visual field changes were observed in 12.4% of patients treated with pregabalin and 11.7% of patients in the placebo group. Fundus changes were observed in 1.7% of patients treated with pregabalin and 2.1% of patients in the placebo group.
Fibromyalgia.
The efficacy of pregabalin was established in one 14-week, double-blind, placebo-controlled, multicenter study and one 6-week, randomized withdrawal study. These studies enrolled patients diagnosed with fibromyalgia based on the American College of Rheumatology criteria (3-month history of widespread pain and pain present in 11 or more of 18 specific tender points). The studies demonstrated a reduction in pain on a visual analog scale. Improvement was additionally demonstrated on the patient's global assessment and on a fibromyalgia impact questionnaire.
Children: A 15-week placebo-controlled study was conducted in 107 children aged 12 to 17 years with fibromyalgia who received pregabalin at a dose of 75 to 450 mg/day. The primary efficacy endpoint (change in total pain intensity from baseline to week 15; calculated using an 11-point rating scale) demonstrated a numerically greater improvement in patients treated with pregabalin compared to patients treated with 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
The steady-state pharmacokinetics of pregabalin were similar in healthy volunteers, patients with epilepsy taking antiepileptic drugs, and patients with chronic pain.
Absorption.
Pregabalin is rapidly absorbed in the fasted state and reaches peak plasma concentrations within 1 hour after single and multiple dosing. The estimated oral bioavailability of pregabalin is greater than 90% and is independent of dose. Steady state is reached within 24–48 hours after multiple dosing. The rate of absorption of pregabalin is reduced when taken with food, resulting in a decrease in maximum concentration (Cmax) of approximately 25–30% and a delay in tmax of approximately 2.5 hours. However, taking pregabalin with food had no clinically significant effect on the extent of its absorption.
Distribution.
Pregabalin crosses the blood-brain barrier in rats, mice and monkeys. Pregabalin also crosses the placenta in rats and is excreted in the milk of lactating rats. In humans, the apparent volume of distribution of pregabalin after oral administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins. Metabolism.
Pregabalin undergoes minimal metabolism in humans. After administration of a dose of radiolabeled pregabalin, approximately 98% of the radioactivity is excreted in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of the drug detected in urine, accounted for 0.9% of the administered dose. In studies, there was no racemization of the S-enantiomer of pregabalin to the R-enantiomer.
Breeding.
Pregabalin is eliminated from the systemic circulation unchanged primarily by renal excretion. The mean elimination half-life of pregabalin is 6.3 hours. The plasma and renal clearance of pregabalin are directly proportional to creatinine clearance (see section "Pharmacokinetics. Renal impairment").
Patients with impaired renal function or patients on hemodialysis require dose adjustment (see section "Method of administration and dosage", Table 1).
Linearity/nonlinearity.
The pharmacokinetics of pregabalin are linear over the recommended dose range. The variability in the pharmacokinetics of pregabalin within patients is low (less than 20%). The pharmacokinetics of multiple doses are predictable based on data obtained with the administration of a single dose. Therefore, there is no need for routine monitoring of pregabalin plasma concentrations.
Sex.
Research data indicate that there is no clinically significant effect of gender on pregabalin plasma concentrations.
Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (after 4 hours of hemodialysis, the concentration of pregabalin in the blood plasma is reduced by approximately 50%). Since renal excretion is the main route of drug elimination, patients with renal insufficiency should reduce the dose of the drug, and after hemodialysis - take an additional dose (see section "Method of administration and dosage", Table 1).
Liver failure.
Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin is not extensively metabolized and is excreted primarily unchanged in the urine, 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) at 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 in the fasted state, the time to peak plasma concentration was generally similar across age groups and ranged from 0.5 hours to 2 hours post-dose.
Pregabalin Cmax and area under the concentration-time curve (AUC) increased linearly with increasing dose in each age group. In children weighing <30 kg, AUC values were 30% lower, due to a 43% increase in weight-adjusted clearance in these patients compared to patients weighing ≥30 kg.
The terminal half-life of pregabalin averaged approximately 3–4 hours in children under 6 years of age and 4–6 hours in children over 7 years of age.
In a population pharmacokinetic analysis, creatinine clearance was shown to be 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 pediatric and adult patients.
The pharmacokinetics of pregabalin in patients less than 3 months of age have not been studied (see sections 4.2, 4.8, and 4.8).
Elderly patients.
Pregabalin clearance tends to decrease with age. This decrease in oral pregabalin clearance is consistent with the age-related decrease in creatinine clearance. Patients with age-related renal impairment may require a reduction in the dose of pregabalin (see Dosage and Administration, Table 1).
Breast-feeding.
The pharmacokinetics of pregabalin, administered at a dose of 150 mg every 12 hours (300 mg daily dose), were evaluated in 10 lactating women for at least 12 weeks postpartum. Breastfeeding had no or negligible effect on the pharmacokinetics of pregabalin. Pregabalin was excreted in breast milk, with mean steady-state concentrations approximately 76% of maternal plasma concentrations. The estimated dose to the breastfed infant (with a mean milk intake of 150 mL/kg/day) from a woman taking pregabalin at a dose of 300 mg/day or a maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These estimated doses represent approximately 7% of the total maternal daily dose on a mg/kg basis.
Indication
Neuropathic pain.
Gabana® is indicated for the treatment of neuropathic pain of peripheral or central origin in adults.
Epilepsy.
Gabana® is indicated in adults as adjunctive treatment for partial seizures with or without secondary generalization.
Generalized anxiety disorder.
Gabana® is indicated for the treatment of generalized anxiety disorder in adults.
Fibromyalgia.
Contraindication
Hypersensitivity to the active substance or to any of the excipients (see section "Composition").
Interaction with other medicinal products and other types of interactions
Since pregabalin is mainly excreted unchanged in the urine, undergoes little metabolism in humans (less than 2% of the dose is excreted in the urine as metabolites), does not inhibit the metabolism of other drugs in vitro, and does not bind to plasma proteins, it is unlikely that pregabalin can cause or be the target of pharmacokinetic interactions.
Since pregabalin is mainly excreted unchanged in the urine, undergoes little metabolism in humans (less than 2% of the dose is excreted in the urine as metabolites), does not inhibit the metabolism of other drugs in vitro, and does not bind to plasma proteins, it is unlikely that pregabalin can cause or be the target of pharmacokinetic interactions.
In vivo studies have not shown any clinically significant pharmacokinetic interactions between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis has shown that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine and topiramate have no clinically significant effect on the clearance of pregabalin.
Co-administration of pregabalin with oral contraceptives, norethisterone and/or ethinyl estradiol does not affect the steady-state pharmacokinetics of either drug.
Drugs that affect the CNS.
Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical studies, multiple oral administration of pregabalin with oxycodone, lorazepam, or ethanol did not result in clinically significant effects on respiratory function. During post-marketing surveillance, cases of respiratory failure, coma, and death have been reported in patients taking pregabalin with other CNS depressants, particularly in patients who abuse such substances. Pregabalin is likely to potentiate the cognitive and gross motor impairments caused by oxycodone.
Interaction in elderly patients.
No specific pharmacodynamic interaction studies have been conducted in the elderly. Drug interaction studies have only been conducted in adult patients.
Application features
Patients with diabetes.
In accordance with current clinical practice, some patients with diabetes mellitus whose body weight has increased during the use of pregabalin may require dose adjustment of hypoglycemic drugs.
Hypersensitivity reactions.
Hypersensitivity reactions, including angioedema, have been reported. Pregabalin should be discontinued immediately if symptoms of angioedema such as facial swelling, perioral swelling, or upper respiratory tract swelling occur.
Dizziness, drowsiness, loss of consciousness, confusion and mental disorders.
Pregabalin has been associated with dizziness and somnolence, which may increase the risk of falls in elderly patients. Loss of consciousness, confusion, and mental status changes have been reported. Therefore, patients should exercise caution until they are aware of the potential effects of the drug.
Visual impairment.
In studies, blurred vision was reported more frequently in patients treated with pregabalin than in patients treated with placebo. In most cases, this phenomenon resolved with continued use of the drug. The incidence of visual acuity deterioration and visual field changes was higher in patients treated with pregabalin than in patients in the placebo group; the incidence of fundus changes was higher in patients in the placebo group (see section "Pharmacological properties. Pharmacodynamics").
Visual adverse reactions, including loss of vision, blurred vision, or other changes in visual acuity, many of which were transient, have also been reported. Discontinuation of pregabalin may result in resolution or reduction of these visual symptoms.
Kidney failure.
Cases of renal failure have been reported. This effect was sometimes reversible after discontinuation of pregabalin.
Withdrawal of concomitant antiepileptic medications.
Data on the withdrawal of concomitant antiepileptic drugs after seizure control is achieved with the addition of pregabalin are insufficient to switch to pregabalin monotherapy.
Withdrawal symptoms.
Some patients have experienced withdrawal symptoms after discontinuation of short- or long-term treatment with pregabalin. The following events have been reported: insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, nervousness, depression, pain, seizures, hyperhidrosis, and dizziness, which are indicative of physical dependence. This information should be communicated to the patient before starting treatment.
Convulsions, including status epilepticus and grand mal seizures, may occur during treatment with pregabalin or shortly after discontinuation of its use.
Data on pregabalin withdrawal after long-term use indicate that the incidence and severity of withdrawal symptoms may be dose-dependent.
Congestive heart failure.
Congestive heart failure has been reported in some patients taking pregabalin. This reaction has been observed primarily during the treatment of neuropathic pain with pregabalin in elderly patients with cardiovascular disorders. Pregabalin should be used with caution in such patients. This phenomenon may resolve upon discontinuation of pregabalin.
During the treatment of central neuropathic pain due to spinal cord injury, the incidence of adverse reactions in general, adverse reactions from the central nervous system and especially drowsiness was increased. This may be due to the additive effect of concomitant medicinal products (e.g. antispasticity agents) required for the treatment of this condition. This should be taken into account when prescribing pregabalin to such patients.
Suicidal thinking and behavior.
Suicidal ideation and behavior have been reported in patients treated with antiepileptic drugs for certain indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown, and the available data do not exclude the possibility of its existence for pregabalin.
Therefore, patients should be closely monitored for signs of suicidal thinking and behavior and treated appropriately if they develop. Patients (and caregivers of patients) should be advised to seek medical advice if signs of suicidal thinking or behavior emerge.
Deterioration of the function of the lower gastrointestinal tract.
There have been reports of events associated with the deterioration of lower gastrointestinal function (such as intestinal obstruction, paralytic ileus, constipation) following the administration of pregabalin with medicinal products that may cause constipation, such as opioid analgesics. When pregabalin is used in combination with opioids, measures should be taken to prevent constipation (especially in women and the elderly).
Concomitant use with opioids
Caution is advised when pregabalin is used concomitantly with opioids due to the risk of CNS depression (see section 4.5). In controlled clinical trials, patients taking pregabalin concomitantly with an opioid were at increased risk of opioid-related death compared with opioids alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19 - 2.36]). This increased risk was observed at low doses of pregabalin (≤ 300 mg, 1.52 aOR [95% CI, 1.04 - 2.22]), and there was a trend towards a higher risk at high doses of pregabalin (> 300 mg, 2.55 aOR [95% CI, 1.24 - 5.06]).
Misuse, abuse or addiction.
Cases of misuse, abuse and dependence have been reported. The drug should be used with caution in patients with a history of substance abuse; the patient should be monitored for signs of misuse, abuse or dependence on pregabalin (cases of addiction, exceeding the prescribed dose, drug-seeking behavior have been reported).
Encephalopathy.
Encephalopathy occurred predominantly in patients with comorbidities that could cause encephalopathy.
Lactose intolerance.
Gabana® contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Allergic reactions
The drug Gabana® in a dose of 150 mg contains dyes diamond black and ponso 4R (crimson 4R), which may cause allergic reactions.
Ability to influence reaction speed when driving vehicles or other mechanisms
Pregabalin may have minor or moderate influence on the ability to drive and use machines. The drug may cause dizziness and drowsiness, which may affect the ability to drive and use machines. Therefore, patients should be advised to refrain from driving or operating complex machinery or other potentially hazardous activities until it is known whether this drug affects their ability to perform such activities.
Use during pregnancy or breastfeeding
Women of childbearing potential/contraception for women and men.
Since the potential risk to humans is unknown, women of childbearing potential should use effective contraception.
Pregnancy.
There are no adequate data from the use of pregabalin in pregnant women.
Reproductive toxicity has been demonstrated in animal studies. The potential risk to humans is unknown.
Pregabalin preparations should not be used during pregnancy unless clearly necessary (when the benefit to the mother clearly outweighs the potential risk to the fetus).
Breast-feeding.
Small amounts of pregabalin have been detected in the milk of nursing women. Nursing women should be advised that breastfeeding is not recommended while taking pregabalin.
Fertility.
In a clinical study to investigate the effect of pregabalin on sperm motility, healthy male volunteers were administered pregabalin at a dose of 600 mg/day. No effect on sperm motility was observed after 3 months of treatment.
Adverse effects on reproductive function were observed in a fertility study in female rats. Adverse effects on reproductive function and development were observed in a fertility study in male rats. The clinical relevance of these findings is unknown.
Method of administration and doses
Gabana® should be taken regardless of meals.
Gabana® is intended exclusively for oral use.
Doses.
The dose range can vary from 150 to 600 mg per day. The dose is divided into 2 or 3 doses.
If a lower dosage (25 mg or 50 mg) is required, pregabalin should be used in a different dosage form.
Neuropathic pain.
Pregabalin treatment can be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the efficacy and tolerability of the drug by the patient, the dose can be increased to 300 mg per day after an interval of 3 to 7 days, and if necessary, to a maximum dose of 600 mg per day after an additional seven-day interval.
Epilepsy.
Pregabalin treatment can be started at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the effectiveness and tolerability of the drug by the patient, the dose can be increased to 300 mg per day after the first week of treatment. After another week, the dose can be increased to a maximum of 600 mg per day.
Generalized anxiety disorder.
The dose, divided into 2 or 3 doses, can be varied within the range of 150–600 mg per day. The need for continued treatment should be reassessed periodically.
Pregabalin treatment can be started at a dose of 150 mg per day. Depending on the effectiveness and tolerability of the drug by the patient, the dose can be increased to 300 mg per day after the first week of treatment. After another week of treatment, the dose can be increased to 450 mg per day. After another week, the dose can be increased to a maximum of 600 mg per day.
Fibromyalgia.
The recommended dose 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 for whom 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 been conducted with a dose of 600 mg per day, there is no evidence that this dose would provide additional benefit; it was also less well tolerated. Given the dose-related adverse reactions, doses above 450 mg per day are not recommended. Since pregabalin is primarily excreted by the kidneys, the dose should be adjusted in patients with impaired renal function.
Discontinuation of pregabalin treatment.
In accordance with current clinical practice, if necessary, it is recommended to discontinue pregabalin treatment gradually over a period of at least one week, regardless of the indication (see sections “Special precautions” and “Adverse reactions”).
Patients with renal failure.
Pregabalin is eliminated from the systemic circulation unchanged primarily by renal excretion. Since pregabalin clearance is directly proportional to creatinine clearance (see section 5.2), dose reduction in patients with renal impairment should be individualized according to creatinine clearance (CLcr) as shown in Table 1 and determined by the formula:
Pregabalin is effectively removed from plasma by haemodialysis (50% of the drug within 4 hours). For patients on haemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, an additional dose of the drug should be administered immediately after each 4-hour haemodialysis session (see Table 1).
Table 1
Pregabalin dose adjustment according to renal function
Creatinine clearance (CLcr), (ml/min)
Total daily dose of pregabalin *
Dosage regimen
Starting dose (mg/day)
Maximum dose (mg/day)
≥ 60
150
600
Twice or three times a day
≥30–<60
75
300
Twice or three times a day
≥15–<30
25–50
150
Once or twice a day
< 15
25
75
Once a day
Additional dose after hemodialysis (mg)
25
100
Single dose+
* 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 drug.
Patients with liver failure.
No dose adjustment is necessary for patients with hepatic insufficiency (see section "Pharmacokinetics").
Use in elderly patients (over 65 years of age).
Elderly patients may require a reduction in the dose of pregabalin due to decreased renal function (see section 4.4).
The safety and efficacy of Gabana® in children under the age of 18 have not been established. Currently available information is provided in the Adverse Reactions section, as well as in the Pharmacodynamics and Pharmacokinetics sections, but no dosage recommendations can be made for this patient population.
Overdose
The most common adverse reactions reported in cases of pregabalin overdose were drowsiness, confusion, agitation, and restlessness. Convulsions have also been reported.
Cases of coma have been reported occasionally.
Treatment of pregabalin overdose consists of general supportive measures and may include hemodialysis if necessary.
Adverse reactions
In studies, the most common adverse reactions were dizziness and drowsiness. Adverse reactions were usually mild or moderate.
Table 2 lists all adverse reactions that occurred more frequently than placebo and in more than one patient; these adverse reactions are presented 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), frequency unknown (cannot be estimated from the available data). These adverse reactions may also be related to the underlying disease and/or concomitant use of other medicinal products.
During the treatment of central neuropathic pain due to spinal cord injury, the incidence of adverse reactions in general, CNS adverse reactions and especially drowsiness was increased (see section "Special precautions").
Additional adverse reactions reported since pregabalin was marketed are listed below and are indicated in the “Frequency unknown” column.
