Galara

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GALARA (GALARA)

Composition:

Active substance: pregabalin;

1 hard capsule contains pregabalin 75 mg or 150 mg;

Excipients: microcrystalline cellulose type 102, corn starch, talc, magnesium stearate;
Capsule (body and cap): titanium dioxide (E 171), iron oxide red (E 172), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

• 75 mg hard capsules: hard gelatin capsules, size № 4, opaque red-brown cap and opaque white body containing white or almost white powder;
• 150 mg hard capsules: hard gelatin capsules, size № 2, opaque red-brown cap and opaque white body containing white or almost white powder.

Pharmacotherapeutic group.

Analgesics. Other analgesics and antipyretics. Gabapentinoids. Pregabalin.

ATC code N02BF02.

Pharmacological Properties.

Pharmacodynamics.

The active substance is 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

The efficacy of pregabalin has been demonstrated in clinical trials for the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. Its efficacy 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 dosing regimen of twice daily, and in trials lasting up to 8 weeks with a dosing regimen of three times daily. Overall, the safety and efficacy profiles for the twice-daily and three-times-daily regimens were similar.

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

In controlled clinical trials of peripheral neuropathic pain, a 50% improvement on the pain rating scale was observed in 35% of patients receiving pregabalin and in 18% of patients receiving placebo. Among patients who did not experience somnolence, such improvement was observed in 33% of patients receiving pregabalin and in 18% of placebo 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 of central neuropathic pain, a 50% improvement on the pain rating scale was observed in 22% of patients receiving pregabalin and in 7% of patients receiving placebo.

Epilepsy

Adjunctive therapy

Pregabalin was studied in three controlled clinical trials lasting 12 weeks with dosing regimens of twice daily or three times daily. Overall, the safety and efficacy profiles for the twice-daily and three-times-daily regimens were similar.

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

Children

The efficacy and safety of pregabalin as adjunctive therapy in epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study involving patients aged 3 months to 16 years (n = 65) with partial seizures were similar to those in adults. Results from a 12-week placebo-controlled trial involving 295 children aged 4 to 16 years, a 14-day placebo-controlled trial involving 175 children aged 1 month to less than 4 years, assessing the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and two open-label safety studies lasting 1 year involving 54 and 431 children aged 3 months to 16 years with epilepsy indicate that adverse reactions such as pyrexia and upper respiratory tract infections occur more frequently in children than in adult patients with epilepsy (see sections "Pharmacokinetics", "Dosage and administration", and "Adverse reactions").

In the 12-week placebo-controlled trial, children (aged 4 to 16 years) were administered 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. The median daily seizure frequency at baseline and at the final visit was 4.7 and 3.8, respectively, for pregabalin at 7 mg/kg/day, 5.4 and 1.4 for pregabalin at 14 mg/kg/day, and 2.9 and 2.3 for placebo. Pregabalin at 14 mg/kg/day significantly reduced the logarithmically transformed frequency of partial seizures compared to placebo (p = 0.0223); 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. A reduction in PGTC seizure frequency of at least 50% 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, as assessed at 6 months using the 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 relapse prevention trial with a double-blind relapse prevention phase lasting 6 months.

Reduction in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Rating Scale (HAM-A) was observed as early as 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 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 effect resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundoscopic examination with dilated pupils) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity worsened in 6.5% of patients in the pregabalin group and in 4.8% of patients in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and in 11.7% of patients in the placebo group. Fundoscopic changes were observed in 1.7% of patients receiving pregabalin and in 2.1% of patients in the placebo group.

Fibromyalgia

The efficacy of pregabalin was established in one 14-week double-blind placebo-controlled multicenter trial (F1) and one 6-week randomized withdrawal trial (F2). Patients included in these trials had a diagnosis of 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 a reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global assessment and fibromyalgia impact questionnaire.

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

Pharmacokinetics.

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

Absorption

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

Distribution

Preclinical studies have shown that pregabalin crosses the blood-brain barrier in mice, rats, and monkeys. It has been established that pregabalin crosses the placenta in rats and is excreted into the milk of lactating rats. In humans, the volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin does not bind to plasma proteins.

Metabolism

In humans, pregabalin undergoes negligible 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—excreted in urine was 0.9% of the administered dose. During preclinical studies, no racemization of the S-enantiomer of pregabalin to the R-enantiomer occurred.

Excretion

Pregabalin is eliminated from systemic circulation unchanged, primarily via the kidneys. The mean elimination half-life of pregabalin is 6.3 hours. Plasma and renal clearance of pregabalin are directly proportional to creatinine clearance (see section "Pharmacokinetics. Renal impairment").

Dose adjustment of pregabalin is required for patients with renal impairment or patients on hemodialysis (see section "Dosage and administration", table).

Linearity/non-linearity

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

Pharmacokinetics in specific patient populations

Sex

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

Patients with renal impairment

Pregabalin clearance is directly proportional to creatinine clearance. Additionally, pregabalin is effectively removed from plasma by hemodialysis (after 4 hours of hemodialysis, plasma pregabalin concentration decreases by approximately 50%). Since pregabalin is primarily eliminated by the kidneys, dose reduction is necessary for patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Dosage and administration", table).

Patients with hepatic impairment

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes negligible metabolism and is primarily excreted unchanged in urine, it is unlikely that hepatic impairment would have a significant effect on 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, ranging from 0.5 to 2 hours after administration.

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

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

In a population pharmacokinetic analysis, creatinine clearance was a significant covariate for oral pregabalin clearance, and body weight was a significant covariate for the apparent volume of distribution of oral pregabalin, and this relationship was similar in children and adult patients.

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

Elderly patients

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

Women who are breastfeeding

Pregabalin pharmacokinetics after administration of 150 mg every 12 hours (daily dose 300 mg) were evaluated in 10 breastfeeding women at least 12 weeks postpartum. Breastfeeding did not affect or had minimal effect on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk, with 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 woman 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 mother's total daily dose normalized to mg/kg.

Clinical characteristics.

Indications.

Neuropathic pain.

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

Epilepsy.

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

Generalized anxiety disorder.

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

Fibromyalgia.

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

Since pregabalin is predominantly excreted unchanged in urine, undergoes minimal metabolism in humans (≤ 2 % of the dose is excreted in 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 would cause pharmacokinetic interactions or be a target of such interactions.

Drug interaction studies have been conducted only in adult patients.

In vivo studies and population pharmacokinetic analysis

Thus, in in vivo studies, no clinically significant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol. Population pharmacokinetic analysis demonstrated that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate have no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and (or) ethinylestradiol

Concomitant administration of pregabalin with oral contraceptives, norethisterone and (or) ethinylestradiol does not affect the steady-state pharmacokinetics of either agent.

MEDICINAL PRODUCTS AFFECTING THE CNS

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

Interactions in elderly patients

No specific pharmacodynamic interaction studies involving elderly volunteers have been conducted.

Special precautions for use.

Patients with diabetes mellitus

According to current clinical practice, some patients with diabetes mellitus who experience weight gain during pregabalin therapy may require adjustment of their antidiabetic medication doses.

Hypersensitivity reactions

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

Skin reactions

Rare cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with pregabalin use, which 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 therapy 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 (e.g., falls) in elderly patients. Cases of loss of consciousness, confusion, and psychiatric disturbances have been reported in the post-marketing period. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of this medicinal product.

Visual disorders

During controlled clinical trials, blurred vision occurred more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this phenomenon resolved with continued therapy. In clinical studies involving ophthalmological examinations, the incidence of decreased visual acuity and visual field changes was higher in patients receiving pregabalin compared to placebo group patients; however, the incidence of fundus changes was higher in the placebo group (see section "Pharmacodynamics").

In the post-marketing period, adverse reactions related to the eye, including vision loss, blurred vision, or other changes in visual acuity, have been reported, many of which were transient. These ocular symptoms may resolve or diminish after discontinuation of pregabalin.

Renal impairment

Cases of renal impairment, sometimes reversible upon discontinuation of pregabalin, have been reported.

Discontinuation of concomitant antiepileptic drugs

There is insufficient data on whether concomitant antiepileptic drugs can be discontinued after seizure control has been achieved with the addition of pregabalin, to switch to pregabalin monotherapy.

Withdrawal symptoms

Withdrawal symptoms have been observed in some patients after discontinuation of short-term or long-term pregabalin therapy. Reported events include insomnia, headache, nausea, anxiety, diarrhoea, flu-like symptoms, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness, indicating physical 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 therapy.

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 "Posology and method of administration").

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

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

Congestive heart failure

Congestive heart failure has been reported in the post-marketing period in some patients taking pregabalin. This reaction was mostly observed during treatment of neuropathic pain in elderly patients with pre-existing cardiovascular disorders. Pregabalin should be used with caution in such patients. This condition may resolve upon discontinuation of pregabalin.

Treatment of central neuropathic pain due to spinal cord injury

During treatment of central neuropathic pain due to spinal cord injury, the overall frequency of adverse reactions, particularly those affecting the CNS such as somnolence, increased. This may be related to the additive effects of concomitant medications (e.g., antispastic agents) required for managing this condition. This should be taken into account when prescribing pregabalin for this indication.

Respiratory depression

Cases of severe respiratory depression have been reported in association with pregabalin use. Patients with impaired respiratory function, respiratory or neurological disorders, renal impairment, concomitant use of CNS depressants, and elderly patients may be at higher risk of this serious adverse reaction. Dose adjustments may be required for these patients.

Suicidal thoughts and behaviour

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

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

Worsening of lower gastrointestinal tract function

In the post-marketing period, events related to impaired lower gastrointestinal tract function (intestinal obstruction, paralytic ileus, constipation) have been reported with pregabalin use, particularly when used concomitantly with medications that may cause constipation, such as opioid analgesics. Preventive measures for constipation should be taken when pregabalin is used with opioids (especially in women and elderly patients).

Concomitant use with opioids

The medicinal product 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 a case-control study of individuals using opioids, an increased risk of opioid-related mortality was observed in patients taking pregabalin with an opioid 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 higher risk at higher pregabalin doses (> 300 mg, aOR 2.55 [95% CI 1.24–5.06]).

Misuse, abuse, or dependence

Pregabalin may lead to drug dependence, including when used at therapeutic doses. Cases of misuse and abuse have been reported. Patients with a history of substance abuse are at increased risk of misuse, abuse, or dependence on pregabalin and should be treated with caution. A careful assessment of the patient’s risk for misuse, abuse, or dependence on pregabalin should be performed before initiating treatment. Patients should be monitored during treatment for signs of misuse, abuse, or dependence, such as development of tolerance, exceeding prescribed doses, or 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 unborn child. The medicinal product should not be used during pregnancy unless clearly necessary and the expected benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment (see section "Pregnancy and breastfeeding").

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception.

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

Pregnancy

Reproductive toxicity has been demonstrated in animal studies.

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

Major congenital malformations (MCM)

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

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

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

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

Breastfeeding

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

Fertility

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

No effect of pregabalin on sperm motility was detected in healthy male volunteers receiving 600 mg daily for 3 months.

Fertility studies demonstrated negative effects on reproductive function in female rats and negative effects on reproductive function and development in male rats. The clinical relevance of these findings is unknown.

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Method of Administration

The medicinal product is intended for oral administration. Capsules should be taken independently of food intake.

Dosage

The dose range of the drug 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 individual response and tolerability of pregabalin, the dose may be increased to 300 mg per day after 3–7 days, and if necessary, to the maximum dose of 600 mg per day after another 7 days.

Epilepsy

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on the individual response and tolerability of the drug, 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 range from 150 to 600 mg per day. The need for continued therapy should be periodically reassessed.

Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on the individual response and tolerability of pregabalin, 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 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 for the treatment of fibromyalgia ranges from 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 the use of a 600 mg daily dose, there is no evidence that this dose provides additional benefit; furthermore, this dose was associated with poorer tolerability. Given the dose-dependent adverse reactions, doses above 450 mg per day are not recommended.

Since pregabalin is primarily eliminated via the kidneys, dosage adjustment is required in patients with renal impairment.

Discontinuation of Pregabalin Therapy

According to current clinical practice, pregabalin therapy should be discontinued gradually over at least one week, regardless of the indication (see sections "Special Warnings and Precautions" and "Adverse Reactions").

Patients with Renal Impairment

Pregabalin is eliminated from systemic circulation unchanged, predominantly via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage reduction in patients with renal impairment should be individualized according to creatinine clearance (CLcr), as indicated in the table below, 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 extra dose of the drug should be administered immediately after each 4-hour hemodialysis session (see table).

Dosage Adjustment of Pregabalin According to Renal Function

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

+Additional dose – an extra single dose.

Patients with hepatic impairment

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

Use in elderly patients

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

Children

The safety and efficacy of pregabalin in pediatric patients (under 18 years of age) have not been established. Available data are presented in section "Adverse reactions" as well as in sections "Pharmacodynamics" and "Pharmacokinetics"; however, based on this information, no dosage recommendations can be provided for this patient group.

Overdose.

The most commonly reported adverse reactions in cases of 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 "Dosage and administration", table).

Adverse Reactions

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

Below is a list of all adverse reactions occurring more frequently than with placebo and in more than one patient. These adverse reactions are categorized by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

The listed adverse reactions may also be related to the underlying disease and/or concomitant use of other medicinal products.

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

Additional adverse reactions reported after pregabalin marketing are listed below and marked in italics.

Infections and infestations:

common – nasopharyngitis.

Blood and lymphatic system disorders:

uncommon – neutropenia.

Immune system disorders:

uncommon – hypersensitivity reactions; rare – angioedema, allergic reactions, anaphylactoid reactions.

Metabolism and nutrition disorders:

common – increased appetite; uncommon – loss of appetite, hypoglycemia.

Psychiatric disorders:

common – euphoric mood, confusion, irritability, disorientation, insomnia, decreased libido; uncommon – hallucinations, panic attacks, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood changes, depersonalization, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy; rare – disinhibition, suicidal ideation and behavior; frequency not known – drug dependence.

Nervous system disorders:

very common – dizziness, somnolence, headache; common – ataxia, coordination disorder, 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 impairment, psychiatric disorders, speech disorders, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, apathy, perioral paresthesia, myoclonus; rare: seizures, parosmia, hypokinesia, dysphagia, hypalgesia, dependence, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal syndrome, Guillain-Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders, parkinsonism.

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 – vision 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; rare – prolongation of the QT interval, sinus tachycardia, sinus arrhythmia.

Vascular disorders:

uncommon – arterial hypotension, arterial hypertension, flushing, hyperemia, cold sensation in extremities.

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, sneezing; frequency not known – 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 – hepatic failure, hepatitis.

Skin and subcutaneous tissue disorders:

common – pressure ulcers; uncommon – papular rash, urticaria, hyperhidrosis, itching, alopecia, dry skin, eczema, hirsutism, skin ulcers, vesiculobullous rash; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, cold sweat, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail disorders, petechial rash, purpura, pustular eruptions, skin atrophy, skin necrosis, skin and subcutaneous nodules.

Musculoskeletal and connective tissue disorders:

common – muscle cramps, arthralgia, back pain, limb pain, neck muscle spasms; uncommon – joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness; rare – rhabdomyolysis.

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 delay, dysmenorrhea, breast pain, leukorrhea, menorrhagia, metrorrhagia; rare – amenorrhea, galactorrhea, breast enlargement, gynecomastia, cervicitis, balanitis, epididymitis.

General disorders and administration site conditions:

common – peripheral edema, edema, gait disturbance, falls, feeling drunk, unusual sensations, fatigue; uncommon – generalized edema, facial swelling, chest tightness, pain, warmth, thirst, chills, general weakness, malaise, abscess, lipodermatitis, 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).

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

Data on discontinuation of pregabalin after long-term use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration").

Paediatric population

The safety profile of pregabalin established in five studies involving paediatric patients with partial seizures with or without secondary generalization (a 12-week efficacy and safety study in patients aged 4 to 16 years, n = 295; a 14-day efficacy and safety study in patients aged 1 month to less than 4 years, n = 175; a pharmacokinetic and tolerability study, n = 65; and two open-label, one-year safety studies, n = 54 and n = 431) was similar to that observed in adult epilepsy studies. The most commonly observed adverse reactions in the 12-week pregabalin treatment study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis. The most commonly observed adverse reactions in the 14-day pregabalin treatment 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 medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging.

14 capsules in a blister; 1 or 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICIN ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey /
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing authorization holder.

LLC «UORLD MEDICIN», Ukraine /
WORLD MEDICINE, LLC, Ukraine.