Pregadol

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

Composition:

Active ingredient: pregabalin;

1 capsule contains 75 mg or 150 mg or 300 mg of pregabalin;

Excipients: maize starch, talc;

capsule shell composition for 75 mg capsule: gelatin, titanium dioxide (E 171), red iron oxide (E 172);

capsule shell composition for 150 mg capsule: gelatin, titanium dioxide (E 171);

capsule shell composition for 300 mg capsule: gelatin, titanium dioxide (E 171), red iron oxide (E 172).

Pharmaceutical form. Capsules.

Main physicochemical properties:

• 75 mg capsules: hard, opaque gelatin capsules with a red-brown cap and a white body. The capsule content is a white or almost white powder;
• 150 mg capsules: hard, opaque gelatin capsules with a white cap and a white body. The capsule content is a white or almost white powder;
• 300 mg capsules: hard, opaque gelatin capsules with a red-brown cap and a white body. The capsule content is a white or almost white powder.

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

Pharmacological Properties.

Pharmacodynamics.

The active substance, pregabalin, 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.

Studies have demonstrated that the drug is effective in the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of pregabalin in other types of neuropathic pain has not been studied.

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

In clinical trials lasting up to 12 weeks, when pregabalin was used to treat neuropathic pain due to peripheral and central nervous system injury, pain reduction was observed after the first week and persisted throughout the treatment period.

In controlled clinical trials studying peripheral neuropathic pain, 50% improvement on the pain assessment scale was observed in 35% of patients receiving pregabalin and in 18% of patients in the placebo group. Among patients who did not experience somnolence, such improvement was observed in 33% of the pregabalin group and 18% of the placebo group. Among patients who experienced somnolence, the proportion of treatment responders was 48% in the pregabalin group and 16% in the placebo group.

In controlled clinical trials studying centrally mediated neuropathic pain, 50% improvement on the pain assessment scale was observed in 22% of patients receiving pregabalin and in 7% of patients in the placebo group.

• Epilepsy.

Adjunctive therapy.

Pregabalin was studied in 3 controlled clinical trials lasting 12 weeks with twice-daily or three-times-daily dosing regimens. Overall, the safety profile and efficacy were similar for both dosing regimens.

Reduction in seizure frequency was observed during the first week.

Children

The efficacy and safety of pregabalin as an adjunctive treatment for epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study including patients aged 3 months to 16 years (n=65) with partial seizures were similar to those in adults. Results from a 12-week placebo-controlled 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, designed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and two open-label safety studies of 1 year duration involving 54 and 431 children respectively, aged 3 months to 16 years with epilepsy, indicate that adverse reactions such as pyrexia and upper respiratory tract infections occur more frequently in children than in adult patients with epilepsy (see sections "Posology and method of administration", "Undesirable effects", and "Pharmacokinetics").

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 compared to 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. The median daily seizure frequency at baseline and at the final visit was 4.7 and 3.8, respectively, with pregabalin at 7 mg/kg/day; 5.4 and 1.4 with pregabalin at 14 mg/kg/day; and 2.9 and 2.3 with 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 study involving patients with primary generalized tonic-clonic (PGTC) seizures, 219 patients aged 5 to 65 years (including 66 aged 5 to 16 years) received pregabalin at 5 mg/kg/day (maximum 300 mg/day), 10 mg/kg/day (maximum 600 mg/day), or placebo as adjunctive therapy. At least a 50% reduction in PGTC seizure frequency was observed in 41.3%, 38.9%, and 41.7% of patients receiving pregabalin at 5 mg/kg/day, pregabalin at 10 mg/kg/day, and placebo, respectively.

Monotherapy (for 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 superior efficacy compared to lamotrigine in the 6-month assessment of the primary endpoint—seizure freedom. Pregabalin and lamotrigine were equally safe and well tolerated.

• Generalized anxiety disorder.

Pregabalin was studied in 6 controlled trials lasting 4–6 weeks, one 8-week trial involving elderly patients, and one long-term trial evaluating relapse prevention with a 6-month double-blind phase.

Improvement in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Rating Scale (HAM-A) was observed during the first week.

In controlled clinical trials (lasting 4–8 weeks), at least a 50% improvement in the total HAM-A score from baseline to endpoint was observed in 52% of patients receiving pregabalin and 38% of patients in the placebo group.

During controlled trials, blurred vision was reported more frequently by patients taking pregabalin compared to those receiving placebo. In most cases, this effect resolved with continued treatment. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundus examination with dilated pupils) were performed in over 3600 patients during controlled clinical trials. Among these patients, visual acuity worsened in 6.5% of those receiving pregabalin and 4.8% of those in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and 11.7% of those in the placebo group. Fundus changes were observed in 1.7% of patients taking pregabalin and 2.1% of those 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 enrolled in these trials had a diagnosis of 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 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 primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured on 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 and reaches maximum plasma concentrations within 1 hour after single and multiple doses. The calculated oral bioavailability of pregabalin is 90% or more and is dose-independent. At steady state, achieved after 24–48 hours of multiple dosing. The absorption rate of pregabalin is reduced when taken with food, resulting in approximately a 25–30% reduction in maximum concentration (Cmax) and a prolongation of tmax by approximately 2.5 hours. However, co-administration of pregabalin with food does not have a clinically significant effect on the extent of its absorption.

Distribution.

Preclinical studies showed that pregabalin crosses the blood-brain barrier in animals. Pregabalin also crosses the placenta in animals and into animal milk during lactation. 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 radioactivity is excreted in urine as unchanged pregabalin. The N-methylated derivative of pregabalin is the main metabolite detected in urine, accounting for 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 impaired renal function and for patients on hemodialysis (see section "Posology and method of administration", Table 1).

Linearity/non-linearity.

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

Gender.

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

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 concentration of pregabalin decreases by approximately 50%). Since renal excretion is the main route of elimination, 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 primarily excreted unchanged in urine, it is unlikely that hepatic impairment would significantly affect plasma concentrations of pregabalin.

Children

The pharmacokinetics of pregabalin were evaluated in children with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years, and 12 to 16 years) receiving doses of 2.5 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, and 15 mg/kg/day in a pharmacokinetic and tolerability study.

After oral administration of pregabalin to children on an empty stomach, the time to reach Cmax in plasma was generally similar across all age groups, ranging from 0.5 to 2 hours after administration.

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

The terminal t1/2 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 demonstrated that creatinine clearance was a significant covariate for oral pregabalin clearance, and body weight was a significant covariate for apparent volume of distribution of oral pregabalin, and this relationship was similar in children and adult patients.

The pharmacokinetics of pregabalin in patients under 3 months of age have not been studied (see sections "Pharmacodynamics", "Posology and method of administration", and "Undesirable effects").

Elderly patients (aged 65 years and older)

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 a reduced dose of pregabalin (see section "Posology and method of administration", Table).

Lactation period

The pharmacokinetics of pregabalin administered at a dose of 150 mg every 12 hours (daily dose 300 mg) were evaluated in 10 breastfeeding women at least 12 weeks postpartum. Breastfeeding did not affect or had minimal effect on the pharmacokinetics of pregabalin. Pregabalin was excreted into breast milk, with average steady-state concentrations approximately 76% of maternal plasma concentrations. The calculated infant dose received via breast milk (assuming average milk intake of 150 mL/kg/day) from a woman taking pregabalin at 300 mg/day or 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 maternal daily dose normalized to mg/kg.

Clinical characteristics.

Indications.

Neuropathic pain.

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

Epilepsy.

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

Generalized anxiety disorder.

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

Fibromyalgia.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

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

In vivo studies and population pharmacokinetic analysis.

In in vivo studies, no clinically significant pharmacokinetic interaction was observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol. Population pharmacokinetic analysis showed that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate 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 enhance the effects of ethanol and lorazepam. In controlled clinical trials, concomitant administration of multiple oral doses of pregabalin with oxycodone, lorazepam, or ethanol did not result in a clinically significant effect on respiratory function. Post-marketing reports have described cases of respiratory depression and coma in patients who took pregabalin together with other medicinal products that depress central nervous system function. Pregabalin is likely to enhance the cognitive and gross motor function impairment caused by oxycodone.

Elderly patients.

No specific pharmacodynamic interaction studies involving elderly volunteers have been conducted. Interaction studies have been performed only in adults.

Special precautions for use.

Patients with diabetes mellitus

Some patients with diabetes mellitus who experienced weight gain during pregabalin therapy may require adjustment of their antidiabetic medication dosage.

Hypersensitivity reactions

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

Serious skin reactions (SSRs)

Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been rarely reported during pregabalin treatment. These reactions may be life-threatening or fatal. Patients should be informed about the signs and symptoms of such reactions, and closely monitored for the development of skin reactions. If signs or symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative treatment considered (if necessary).

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

Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of accidental injury (e.g., falls) in elderly patients.

Cases of loss of consciousness, confusion, impaired mental function, and cognitive disturbances have been reported. Patients should be advised to exercise caution until they become familiar with the potential effects of the medicinal product.

Visual disorders

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

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. Discontinuation of pregabalin may lead to resolution or reduction of these ocular symptoms.

Renal impairment

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

Discontinuation of concomitant antiepileptic drugs

There is insufficient data on the withdrawal of concomitant antiepileptic drugs after seizure control has been achieved by adding pregabalin to ongoing treatment, with the aim of switching to pregabalin monotherapy.

Heart failure

Cases of congestive heart failure have been observed in some patients taking pregabalin. This reaction was mostly reported during pregabalin treatment for 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

When treating central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, particularly those affecting the central nervous system and especially somnolence, was increased. This may be related to the additive effects of concomitant medications (e.g., antispastic agents) required for the management of this condition. These data should be considered when prescribing pregabalin to such patients.

Respiratory depression

Severe respiratory depression has been reported in association with pregabalin treatment. Patients with respiratory, neurological or renal disorders, those taking other central nervous system (CNS)-depressant medicinal products, or elderly patients may be at higher risk of this serious adverse reaction. Dose adjustment may be necessary in these patient groups.

Suicidal ideation and behaviour

Cases of suicidal ideation 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 showed a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is unknown, and available data do not exclude its existence with the use of pregabalin.

Post-marketing reports have described cases of suicidal ideation and behaviour in patients receiving pregabalin (see section "Adverse reactions"). An epidemiological study using a self-controlled design (comparing treatment periods with non-treatment periods within individual patients) 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 advice if signs of suicidal ideation or behaviour occur. Patients should be monitored for the emergence of suicidal thoughts or behaviour, and appropriate treatment considered. In cases of suicidal ideation or behaviour, discontinuation of pregabalin therapy should be considered.

Worsening of lower gastrointestinal tract function

Post-marketing reports have described events related to worsening of lower gastrointestinal tract function (intestinal obstruction, paralytic ileus, constipation) following pregabalin use in combination with medicinal products that may cause constipation, such as opioid analgesics. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be implemented (particularly in women and elderly patients).

Concomitant use with opioids

Caution is recommended when prescribing pregabalin 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 opioid users, an increased risk of opioid-related mortality was observed in patients receiving pregabalin together with an opioid compared to those receiving 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 higher risk at higher doses (> 300 mg, aOR 2.55 [95% CI 1.24–5.06]).

Misuse, abuse, or dependence

Pregabalin may lead to drug dependence, even when used at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance abuse may be at increased risk of pregabalin misuse, abuse, and dependence, and therefore pregabalin should be used with caution in such patients. Before prescribing pregabalin, the risk of misuse, abuse, or dependence should be carefully assessed.

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

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 symptoms, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness, indicating drug dependence. The occurrence of withdrawal symptoms after pregabalin discontinuation may indicate drug dependence (see section "Adverse reactions"). This information should be communicated to patients prior to initiating therapy.

If pregabalin therapy needs to be discontinued, it is recommended to do so gradually over at least one week, regardless of the indication (see section "Dosage and administration").

Seizures, including epileptic status and generalized tonic-clonic seizures, may occur during pregabalin therapy or shortly after its discontinuation.

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

Encephalopathy

Encephalopathy has occurred 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").

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraceptive methods for women and men.

Women of childbearing potential should use effective contraception.

Pregnancy.

Animal studies have shown reproductive toxicity.

Pregabalin has been shown to cross the placenta in rats.

Pregabalin may cross the human placenta.

Major congenital malformations

Data from a Scandinavian observational study of over 2,700 pregnancies exposed to pregabalin in the first trimester showed a higher prevalence of major congenital malformations among the paediatric population (live or stillborn) compared to the unexposed population (5.9% vs. 4.1%). The risk of major congenital malformations in the paediatric population exposed to pregabalin in the first trimester was slightly higher compared to the unexposed population (adjusted prevalence ratio and 95% confidence interval: 1.14 (0.96–1.35)) and 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 a higher risk of nervous system malformations, eye malformations, orofacial clefts, and genitourinary malformations, although numbers were small and estimates imprecise. Pregabalin should not be used during pregnancy unless clearly necessary (i.e., when benefit to the mother clearly outweighs the potential risk to the fetus).

Breastfeeding.

Pregabalin passes into breast milk. The effect of pregabalin on newborns/infants is unknown. A decision must be made whether to discontinue breastfeeding or to discontinue pregabalin therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Reproductive function

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

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

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

Ability to affect driving or operating machinery.

Pregabalin may have a minor or moderate influence on the ability to drive or operate machinery. Pregabalin may cause dizziness and somnolence and thereby affect the ability to drive or operate machinery. 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 tasks.

Method of Administration and Dosage

Pregadol should be taken regardless of food intake.

This medicinal product is intended for oral use only.

Doses

The dosage range is from 150 to 600 mg per day. The daily dose should be divided into 2 or 3 administrations. For convenient administration of doses < 300 mg per dose, it is recommended to use Pregadol 75 mg capsules, Pregadol 150 mg capsules, or other medicinal products containing pregabalin in appropriate strengths.

Neuropathic pain.

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

Generalized anxiety disorder.

The dose, divided into 2 or 3 administrations, may range from 150 to 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 individual tolerability, the dose may be increased to 300 mg per day after the first week of treatment. After another week of pregabalin administration, 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 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 who do not achieve sufficient efficacy with a dose of 300 mg per day, 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 Pregadol is primarily eliminated via the kidneys, dosage adjustment is required in patients with renal impairment.

Discontinuation of pregabalin treatment.

According to current clinical practice, pregabalin treatment should be discontinued gradually over at least 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 via renal excretion. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dose reduction in patients with impaired renal function should be individualized according to creatinine clearance (CLcr), 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 1).

Table 1

Dosage adjustment of pregabalin according to renal function

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

** Pregabalin should be administered in the appropriate dosage form.

Patients with hepatic impairment.

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

Use in elderly patients (aged 65 years and older).

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

Children.

The safety and efficacy of pregabalin in children (under 18 years of age) have not been established. Available information is presented in sections "Pharmacodynamics", "Pharmacokinetics", and "Side effects"; however, based on this information, no dosage recommendations can be provided for this patient population.

Overdose.

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

Treatment of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis (see section "Dosage and administration", Table 1).

Adverse reactions.

In the clinical program investigating pregabalin, over 8900 patients received the drug, of whom 5600 were participants in double-blind, placebo-controlled studies. The most common adverse reactions were dizziness and somnolence. Adverse reactions were generally mild or moderate in severity.

In all controlled studies, 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 withdrawal from the pregabalin treatment group were dizziness and somnolence.

Below are listed all adverse reactions occurring more frequently than with placebo and in more than one patient, 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). Within each frequency category, adverse reactions are listed in order of decreasing severity.

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

During treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, CNS-related adverse reactions, and particularly somnolence, was increased (see section "Special precautions for use").

Additional adverse reactions reported after pregabalin marketing authorization are indicated in italics in the "Frequency not known" category.

Infections and infestations

Common: nasopharyngitis.

Blood and lymphatic system disorders

Uncommon: neutropenia.

Immune system disorders

Uncommon: hypersensitivity.

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 dysfunction, mental impairment, speech disorders, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, perioral paresthesia, myoclonus.

Rare: seizures, parosmia, hypokinesia, dysgraphia, hypalgesia, dependence, cerebellar syndrome, cogwheel rigidity, 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, ocular hemorrhage, photophobia, retinal edema.

Rare: vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcer, exophthalmos, oculomotor nerve 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.

Isolated cases: sinus tachycardia, sinus bradycardia, sinus arrhythmia, cold sensation in extremities.

Frequency not known: congestive heart failure, QT interval prolongation.

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 not known: pulmonary edema.

Gastrointestinal disorders

Common: vomiting, nausea, constipation, diarrhea, flatulence, abdominal distension, dry mouth, gastroenteritis.

Uncommon: gastroesophageal reflux disease, hypersalivation, oral hypesthesia, 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: Stevens-Johnson syndrome, toxic epidermal necrolysis, 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 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, fall, feeling drunk, unusual sensations, increased fatigue.

Uncommon: generalized edema, facial swelling, chest tightness, pain, pyrexia, thirst, chills, asthenia, malaise, abscess, lipodermatitis, photosensitivity reactions.

Rare: granuloma, self-harm, retroperitoneal fibrosis, shock.

Investigations

Common: weight gain.

Uncommon: increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, weight loss.

Rare: decreased blood leukocyte count.

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

In some patients, withdrawal symptoms were observed after discontinuation of short-term or long-term pregabalin therapy. Reported events included insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, nervousness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness, indicating physical dependence. This information should be communicated to the patient prior to starting therapy.

Data on pregabalin discontinuation 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 four 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 4 years, n=175; a pharmacokinetic and tolerability study, n=65; and a 1-year open-label safety study, n=54) was similar to that observed in studies in adult epilepsy patients. The most commonly observed adverse events 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 events in the 14-day pregabalin treatment study were somnolence, upper respiratory tract infections, and pyrexia (see sections "Dosage and administration", "Pharmacodynamics", and "Pharmacokinetics").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aіsf.dec.gov.ua.

Shelf life.

Capsules 75 mg, 150 mg: 2 years.

Capsules 300 mg: 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

Capsules 75 mg, 150 mg: 10 capsules per blister, 3 or 6 blisters per pack.

Capsules 300 mg: 10 capsules per blister, 3 blisters per pack.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchahivskyy Chemical and Pharmaceutical Plant".

Manufacturer's location and address of business activity.

17 Myru Street, Kyiv, 03134, Ukraine.