Gabana
Ukraine
Table of Contents
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.
Pharmaceutical form. Capsules.
Main physicochemical properties:
- 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 in other types of neuropathic pain has not been studied.
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 pain was observed after the first week and persisted throughout the treatment period.
In controlled clinical trials studying 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 in 18% of patients in the placebo group. Among patients who experienced somnolence, the proportion of responders was 48% in the pregabalin group and 16% in the placebo group.
In a controlled clinical trial studying centrally mediated 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 a twice-daily or three-times-daily dosing regimen. 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 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 study involving 295 children aged 4 to 16 years and a 14-day placebo-controlled study involving 175 children aged 1 month to less than 4 years, aimed at evaluating the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, as well as two open-label safety studies lasting 1 year 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", "Posology and method of administration", and "Undesirable effects").
In the 12-week placebo-controlled study, 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 study, 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 study 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 log-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 study 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) or 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. Pregabalin did not achieve comparable efficacy to lamotrigine, as assessed by the 6-month endpoint of 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 assessing relapse prevention 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), a ≥50% improvement in 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 worsened in 6.5% of patients in the pregabalin group and in 4.8% of patients in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and in 11.7% of patients in the placebo group. Fundus changes were observed in 1.7% of patients receiving pregabalin and in 2.1% of patients in the placebo group.
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 included patients diagnosed with fibromyalgia based on American College of Rheumatology criteria (widespread pain for at least 3 months and pain in 11 or more of 18 specific tender points). The studies demonstrated reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global impression and fibromyalgia impact questionnaire.
Children. A placebo-controlled study was conducted in 107 children aged 12–17 years with fibromyalgia, who received pregabalin at doses of 75–450 mg/day for 15 weeks. Results of the primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured on an 11-point rating scale) showed numerically greater improvement 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 when administered on an empty stomach and reaches maximum plasma concentration (Cmax) within 1 hour after single and multiple doses. The estimated oral bioavailability of pregabalin is 90% or more and is dose-independent. At steady state, achieved after multiple doses, is reached within 24–48 hours. 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 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 metabolite of pregabalin—the main metabolite of the medicinal product—detected in urine was 0.9% of the administered dose. Racemization of the S-enantiomer of pregabalin to the R-enantiomer did not occur during preclinical studies.
Elimination
Pregabalin is eliminated from systemic circulation unchanged, primarily via 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").
Dosage adjustment is required for patients with renal impairment or patients on hemodialysis (see section "Posology and method of 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%). Pharmacokinetics of multiple doses are predictable based on data obtained from single-dose administration. Therefore, routine monitoring of plasma pregabalin concentrations is not required.
Gender
Clinical trial data indicate no clinically significant effect of gender on plasma concentrations of pregabalin.
Renal impairment
Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (after 4 hours of hemodialysis, plasma pregabalin concentration decreases by approximately 50%). Since renal excretion is the main route of elimination of pregabalin, dosage reduction is required for patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Posology and method of 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 plasma concentrations of pregabalin.
Children
Pregabalin pharmacokinetics 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 dose escalation 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.
Pregabalin pharmacokinetics have not been studied in patients under 3 months of age (see sections "Pharmacodynamics", "Posology and method of administration", and "Undesirable effects").
Elderly patients
Pregabalin clearance tends to decrease with age. This decrease in oral pregabalin clearance is consistent with age-related decline in creatinine clearance. Elderly patients with age-related renal impairment may require dosage reduction of pregabalin (see section "Posology and method of administration", Table 1).
Lactation
Pregabalin pharmacokinetics 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 pregabalin pharmacokinetics. Pregabalin passed into breast milk, with average steady-state concentrations approximately 76% of maternal plasma concentrations. The calculated infant dose from breast milk (assuming average milk intake of 150 mL/kg/day) from a mother taking pregabalin at 300 mg/day or at the maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the 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 the metabolism of other medicinal products in vitro, and does not bind to plasma proteins, it is unlikely that pregabalin may cause or be the object of 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 medicinal product.
Medicinal products affecting the CNS
Pregabalin may potentiate the effects of ethanol and lorazepam. In the post-marketing surveillance period, cases of respiratory depression, coma, and fatal outcomes have been reported in patients who took pregabalin together with opioids and/or other medicinal products that depress CNS function. Pregabalin is likely to enhance cognitive and basic motor function impairment caused by oxycodone.
Interaction in elderly patients
No specific pharmacodynamic interaction studies involving elderly patients have been conducted. Drug interaction studies have been performed only in adult patients.
Special precautions for use
Patients with diabetes mellitus
According to current clinical practice, some patients with diabetes mellitus whose body weight has increased during treatment with pregabalin may require adjustment of their antidiabetic medication.
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.
Severe cutaneous adverse reactions (SCARs)
Severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been rarely reported in association with pregabalin treatment. These reactions may be life-threatening or fatal. Patients should be informed about the signs and symptoms, and skin reactions should be closely monitored during treatment. 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
Treatment with pregabalin 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 also been reported. Therefore, patients should exercise caution until they are aware of the potential effects of the medicinal product.
Visual disorders
In 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 treated with pregabalin compared to placebo; however, the incidence of ocular fundus changes was higher in the placebo group (see section "Pharmacological properties. Pharmacodynamics").
Adverse reactions related to 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 discontinuation of concomitant antiepileptic drugs after seizure control has been achieved with the addition of pregabalin to allow transition 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, indicating 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 patients prior to initiating treatment. If pregabalin therapy needs to be discontinued, it is recommended to do so gradually over at least 1 week, regardless of the indication (see section "Dosage and administration").
Seizures, including status epilepticus and generalized tonic-clonic seizures, may occur during treatment with pregabalin or shortly after discontinuation.
Data on withdrawal of pregabalin after long-term use indicate that the frequency and severity of withdrawal symptoms may depend on the dose.
Heart failure
Cases of congestive heart failure have been reported in some patients taking pregabalin. This reaction was mostly observed during treatment of neuropathic pain with pregabalin in elderly patients with cardiovascular disorders. Pregabalin should be used with caution in such patients. This condition may resolve upon discontinuation of pregabalin.
Treatment of central neuropathic pain due to spinal cord injury
During treatment of central neuropathic pain due to spinal cord injury, the incidence of overall adverse reactions and CNS-related adverse reactions, particularly somnolence, was increased. This may be related to the additive effect 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, those taking concomitant CNS depressants, and elderly patients may be at increased risk of this serious adverse reaction. Dose adjustment may be required for these patients (see section "Dosage and administration").
Suicidal thoughts and behaviour
Cases of suicidal thoughts and behaviour have been reported in patients treated with antiepileptic medicinal products for various indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs 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 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 emerge. Patients should be monitored for the emergence of suicidal thoughts and behaviour, and appropriate treatment should be considered. Discontinuation of pregabalin therapy 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 in combination with medicinal products that may cause constipation, such as opioid analgesics. Preventive measures for constipation should be taken when pregabalin is used concomitantly with opioids (especially in women and elderly patients).
Concomitant use with opioids
Pregabalin should be used with caution when administered concomitantly 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 mortality 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 doses of pregabalin (≤ 300 mg, aOR 1.52 [95% CI, 1.04–2.22]) with a trend toward increased risk at higher doses (> 300 mg, aOR 2.55 [95% CI, 1.24–5.06]).
Misuse, abuse or dependence
Pregabalin may cause drug dependence, which may occur even at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance abuse may be at higher risk of misuse, abuse, or dependence on pregabalin and should therefore be treated with caution. The risk of misuse, abuse, or dependence should be carefully assessed before prescribing pregabalin.
Patients receiving pregabalin should be monitored for signs of misuse, abuse, or dependence, such as development of tolerance, dose escalation, and drug-seeking behaviour.
Encephalopathy
Cases of encephalopathy have been reported, primarily in patients with concomitant conditions that may predispose to encephalopathy.
Women of childbearing potential/contraception
Use of pregabalin 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 "Pregnancy and 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 A), which may cause allergic reactions.
Pregnancy and 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 observed in the paediatric population (live 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. Women who are breastfeeding should be advised that breastfeeding is not recommended during treatment with pregabalin.
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. No effect on sperm motility was observed after 3 months of treatment.
In fertility studies in female rats, adverse effects on reproductive function were observed. In fertility studies in male rats, adverse effects on reproductive function and development were observed. The clinical relevance of these findings is unknown.
Effects on ability to drive and use machines
Pregabalin may have a slight or moderate influence on the ability to drive and use machines. Pregabalin may cause dizziness and somnolence, which may affect the ability to drive and use machines. 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.
Administration and Dosage
Route of Administration
Gabana® should be taken regardless of food intake.
Gabana® is intended for oral use only.
Doses
The dose 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 efficacy and patient tolerance, 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 efficacy and patient tolerance, 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 doses, 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 efficacy and patient tolerance, 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 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 treatment
According to current clinical practice, if pregabalin therapy needs to be discontinued, it is recommended to do so gradually over a minimum of one week, regardless of the indication (see sections "Special precautions" and "Adverse reactions").
Patients with renal impairment
Pregabalin is eliminated from systemic circulation unchanged, predominantly by 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 formula:
Pregabalin is effectively removed from plasma by hemodialysis (50% of the drug within 4 hours). For patients on hemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, an extra 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
| Creatinine clearance (CLcr), (mL/min) |
Total daily dose of pregabalin * |
Dosing regimen |
|
| Initial dose (mg/day) |
Maximum dose (mg/day) |
||
| ≥ 60 |
150 |
600 |
Twice or three times daily |
| ≥30–<60 |
75 |
300 |
Twice or three times daily |
| ≥15–<30 |
25–50 |
150 |
Once or twice daily |
| < 15 |
25 |
75 |
Once daily |
| 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 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 data are presented in the section "Adverse reactions" and also in sections "Pharmacodynamics" and "Pharmacokinetics"; however, based on this information, no dosing recommendations can be provided for this patient population.
Overdose
The most commonly reported adverse reactions following pregabalin overdose were somnolence, confusion, agitation, and restlessness. Seizures have also been reported. Rare cases of coma have been reported.
Treatment of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis (see section "Method of administration and dosage", Table 1).
Adverse Reactions
In the clinical development program for pregabalin, more than 8900 patients received the drug, including 5600 patients 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, including those affecting the central nervous system (CNS), increased, particularly somnolence (see section "Special Warnings and Precautions for Use").
Additional adverse reactions reported after marketing authorization of pregabalin are included in the list below and are designated under the category "Frequency not known."
Table 2
| System Organ Class |
Frequency |
Adverse Reactions |
| Infections and infestations |
Common |
Nasopharyngitis |
| Blood and lymphatic system disorders |
Uncommon |
Neutropenia |
| Immune system disorders |
Uncommon |
Hypersensitivity |
| Rare |
Angioedema, allergic reaction, anaphylactoid reactions |
|
| Metabolism and nutrition disorders |
Common |
Increased appetite |
| Uncommon |
Loss of appetite, hypoglycemia |
|
| Psychiatric disorders |
Common |
Euphoric mood, confusion, irritability, decreased libido, disorientation, insomnia |
| Uncommon |
Hallucinations, panic attacks, excitement, restlessness, depression, depressed mood, elevated mood, aggression, mood swings, depersonalization, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy |
|
| Rare |
Disinhibition, suicidal behavior, suicidal ideation |
|
| Frequency unknown |
Drug dependence |
|
| Nervous system disorders |
Very common |
Dizziness, somnolence, headache |
| Common |
Ataxia, coordination disturbance, tremor, dysarthria, amnesia, memory impairment, attention disturbance, paresthesia, hypesthesia, sedation, balance disorder, lethargy |
|
| Uncommon |
Syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive dysfunction, psychiatric disturbance, speech disorder, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, apathy, perioral paresthesia, myoclonus |
|
| Rare |
Convulsions, parosmia, hypokinesia, dysphagia, parkinsonism, hypalgesia, dependence, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain-Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders |
|
| Eye disorders |
Common |
Blurred vision, diplopia, conjunctivitis |
| Uncommon |
Peripheral vision loss, visual disturbance, eye swelling, visual field defects, reduced visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, blepharitis, accommodation disorder, eye hemorrhage, photophobia, retinal edema |
|
| Rare |
Visual loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcer, exophthalmos, oculomotor paralysis, iritis, keratoconjunctivitis, miosis, night blindness, ophthalmoplegia, optic nerve atrophy, optic disc edema, ptosis, uveitis |
|
| Ear and labyrinth disorders |
Common |
Vertigo |
| Uncommon |
Hyperacusis |
|
| Cardiac disorders |
Uncommon |
Tachycardia, first-degree atrioventricular block, sinus bradycardia, congestive heart failure, arterial hypotension, arterial hypertension, flushing, hyperemia, cold sensation in extremities |
| Rare |
QT interval prolongation, sinus tachycardia, sinus arrhythmia |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Pharyngolaryngeal pain |
| Uncommon |
Dyspnea, epistaxis, cough, nasal congestion, rhinitis, snoring, dryness of nasal mucosa |
|
| Rare |
Pulmonary edema, throat tightness, laryngospasm, apnea, atelectasis, bronchiolitis, hiccups, pulmonary fibrosis, yawning |
|
| Frequency unknown |
Respiratory depression |
|
| Gastrointestinal disorders |
Common |
Vomiting, nausea, constipation, diarrhea, flatulence, abdominal distension, dry mouth, gastroenteritis |
| Uncommon |
Gastroesophageal reflux disease, hypersalivation, oral hypoaesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, tongue swelling, rectal bleeding |
|
| Rare |
Ascites, pancreatitis, tongue swelling, dysphagia, aphthous stomatitis, esophageal ulcer, periodontal abscess |
|
| Hepatobiliary disorders |
Uncommon |
Increased liver enzymes* |
| Rare |
Jaundice |
|
| Very rare |
Liver failure, hepatitis |
|
| Skin and subcutaneous tissue disorders |
Common |
Pressure ulcers |
| Uncommon |
Papular rash, urticaria, hyperhidrosis, pruritus, alopecia, dry skin, eczema, hirsutism, skin ulcers, vesiculobullous rash |
|
| Rare |
Toxic epidermal necrolysis, Stevens-Johnson syndrome, cold sweat, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail disorders, petechial rash, purpura, pustular rash, skin atrophy, skin necrosis, skin and subcutaneous nodules |
|
| Musculoskeletal and connective tissue disorders |
Common |
Muscle spasms, arthralgia, back pain, limb pain, neck muscle spasms |
| Uncommon |
Joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness |
|
| Rare |
Rhabdomyolysis |
|
| Renal and urinary disorders |
Uncommon |
Urinary incontinence, dysuria, albuminuria, hematuria, kidney stone formation, nephritis |
| Rare |
Renal failure, oliguria, urinary retention, acute renal failure, glomerulonephritis, pyelonephritis |
|
| Reproductive system and breast disorders |
Common |
Erectile dysfunction, impotence |
| Uncommon |
Sexual dysfunction, ejaculation delayed, dysmenorrhea, breast pain, leukorrhea, menorrhagia, metrorrhagia |
|
| Rare |
Amenorrhea, galactorrhea, breast enlargement, gynecomastia, cervicitis, balanitis, epididymitis |
|
| General disorders |
Common |
Peripheral edema, edema, gait disturbance, fall, feeling drunk, unusual feelings, increased fatigue |
| Uncommon |
Generalized edema, facial edema, chest tightness, pain, warmth, thirst, chills, general weakness, malaise, abscess, panniculitis, photosensitivity reactions |
|
| Rare |
Granuloma, self-harm, retroperitoneal fibrosis, shock |
|
| Investigations |
Common |
Weight increased |
| Uncommon |
Increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, weight decreased |
|
| Rare |
Decreased blood leukocyte count |
* 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 include 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 withdrawal from pregabalin after long-term 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 suspected adverse reactions after drug registration is important. 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 cases of 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 in a blister, 2 blisters in a carton.
Prescription status
Prescription only.
Manufacturer
JSC "Kyivmedpreparat" – for 25 mg, 50 mg, 75 mg, 150 mg, 300 mg dosages.
LLC "MARIPHARM" – for 75 mg, 150 mg, 300 mg dosages.
Manufacturer's address and location of business activity
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.
8 Minarikova Street, Maribor, 2000, Slovenia.