Pregabio®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Pregabio® (Pregabio®)

Composition:

Active ingredient: pregabalin;

1 capsule contains 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, or 300 mg of pregabalin;

Excipients: pregelatinized starch, talc;

Capsule shell: gelatin, titanium dioxide (E 171), black iron oxide\textsuperscript{1} (E 172), yellow iron oxide\textsuperscript{2} (E 172), red iron oxide\textsuperscript{3} (E 172); black printing ink\textsuperscript{4}: shellac, black iron oxide (E 172), propylene glycol; white printing ink\textsuperscript{5}: shellac, propylene glycol, potassium hydroxide, titanium dioxide (E 171).

\textsuperscript{1} for 200 mg, 225 mg, and 300 mg capsules;
\textsuperscript{2} for 50 mg, 75 mg, 150 mg, 200 mg, 225 mg, and 300 mg capsules;
\textsuperscript{3} for 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg capsules;
\textsuperscript{4} for 25 mg, 50 mg, 75 mg, 150 mg, 200 mg, 225 mg, and 300 mg capsules;
\textsuperscript{5} for 100 mg and 300 mg capsules.

Pharmaceutical form. Capsules.

Main physicochemical properties:

• 25 mg capsules: hard gelatin capsules. The body of the capsule is white, the cap is white. The cap is printed in black ink with "P25". The capsule contains powder ranging from white to almost white. Capsule size No. 4;
• 50 mg capsules: hard gelatin capsules. The body of the capsule is white, the cap is bright yellow. The cap is printed in black ink with "P50". The capsule contains powder ranging from white to almost white. Capsule size No. 3;
• 75 mg capsules: hard gelatin capsules. The body of the capsule is brownish-yellow, the cap is brownish-yellow. The cap is printed in black ink with "P75". The capsule contains powder ranging from white to almost white. Capsule size No. 4;
• 100 mg capsules: hard gelatin capsules. The body of the capsule is reddish-brown, the cap is reddish-brown. The cap is printed in white ink with "P100". The capsule contains powder ranging from white to almost white. Capsule size No. 3;
• 150 mg capsules: hard gelatin capsules. The body of the capsule is white, the cap is yellowish-brown. The cap is printed in black ink with "P150". The capsule contains powder ranging from white to almost white. Capsule size No. 2;
• 200 mg capsules: hard gelatin capsules. The body of the capsule is brown, the cap is brown. The cap is printed in black ink with "P200". The capsule contains powder ranging from white to almost white. Capsule size No. 1;
• 225 mg capsules: hard gelatin capsules. The body of the capsule is white, the cap is brown. The cap is printed in black ink with "P225". The capsule contains powder ranging from white to almost white. Capsule size No. 1;
• 300 mg capsules: hard gelatin capsules. The body of the capsule is white, the cap is dark brown. The cap is printed in white ink with "P300". The capsule contains powder ranging from white to almost white. Capsule size No. 0.

Pharmacotherapeutic group. Agents acting on the nervous system. Analgesics. Other analgesics and antipyretics. Gabapentinoids. Gabapentin. Pregabalin. ATC code N02BF02.

Pharmacological Properties.

Pharmacodynamics.

The active substance, pregabalin, is a structural analogue of gamma-aminobutyric acid [(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 the drug has been demonstrated in clinical trials for 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 evaluated 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 were similar between the twice-daily and three-times-daily dosing regimens.

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 those receiving pregabalin and 18% of those receiving placebo. 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 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 twice-daily or three-times-daily dosing regimens. Overall, safety and efficacy profiles were similar between the two dosing regimens.

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 observed 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, as well as two open-label safety studies of 1 year duration 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 "Dosage and administration", "Adverse reactions", 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, 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 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. When pregabalin was used, it did not achieve equivalent efficacy compared to lamotrigine, as assessed at 6 months by the primary 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, as measured by 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 the 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 fundoscopic examination with dilated pupils) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity decreased in 6.5% of those in the pregabalin group and in 4.8% of those in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and in 11.7% of those in the placebo group. Fundoscopic changes were observed in 1.7% of patients receiving pregabalin and in 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 in one 6-week randomized withdrawal trial (F2). These trials included patients diagnosed with fibromyalgia based on American College of Rheumatology criteria (widespread pain lasting at least 3 months and pain present in 11 or more of 18 specific tender points). The trials demonstrated a reduction in pain measured by 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 in 107 children aged 12–17 years with fibromyalgia, who received pregabalin at doses of 75–450 mg/day. 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 commonly reported 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 peak plasma concentrations within 1 hour after single or multiple doses. The estimated oral bioavailability of pregabalin is ≥ 90% and is dose-independent. Steady-state concentrations are achieved within 24–48 hours with repeated dosing. The rate of pregabalin absorption is reduced when administered with food, resulting in approximately a 25–30% reduction in maximum concentration (Cmax) and an increase in tmax to approximately 2.5 hours. However, administration of pregabalin with food does 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 minimal metabolism. After administration of a radiolabeled dose of pregabalin, approximately 98% of the radioactivity was excreted unchanged in urine. The fraction of the N-methylated metabolite of pregabalin—the main metabolite detected 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").

Dosage adjustment is required for patients with renal impairment or those undergoing hemodialysis (see section "Dosage and administration", Table 1).

Linearity/Non-linearity.

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

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 the drug is primarily eliminated by the kidneys, dosage reduction is required in patients with renal impairment, and a supplemental dose should be administered after hemodialysis (see section "Dosage and administration", Table 1).

Hepatic impairment.

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is excreted predominantly unchanged in urine, it is unlikely that hepatic impairment would have a significant effect on 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, 5, 10, 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 maximum plasma concentration (tmax) was generally similar across all age groups, ranging from 0.5 to 2 hours post-dose.

Cmax and area under the concentration-time curve (AUC) 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 creatinine clearance-adjusted body weight-corrected clearance in these patients compared to those 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 demonstrated that creatinine clearance was a significant covariate for oral pregabalin clearance, and body weight was a significant covariate for the apparent volume of distribution of oral pregabalin, and this relationship was similar in children and adult patients.

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

Elderly patients.

Pregabalin clearance tends to decrease with age. This reduction in oral pregabalin clearance is consistent with 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 1).

Lactation.

The pharmacokinetics of pregabalin were evaluated in 10 breastfeeding women receiving 150 mg every 12 hours (daily dose 300 mg), at least 12 weeks postpartum. Breastfeeding had no effect or only a 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 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.

Treatment of neuropathic pain in adults associated with damage to the peripheral and central nervous system.

Epilepsy.

Adjunctive therapy for partial seizures with or without secondary generalization in adults.

Generalized anxiety disorder.

Treatment of generalized anxiety disorder in adults.

Fibromyalgia.

Treatment of fibromyalgia in adults.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the 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 (≤ 2% of the dose is excreted in urine as metabolites), does not inhibit metabolism of other drugs in vitro, and does not bind to plasma proteins, it is unlikely that pregabalin would cause or be subject to pharmacokinetic interactions.

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 medicinal product.

Medicinal products affecting the CNS.

Pregabalin may potentiate the effects of ethanol and lorazepam. During post-marketing surveillance, 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 central nervous system 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. 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 who experience weight gain during pregabalin therapy may require adjustment of their antidiabetic medication doses.

Hypersensitivity reactions

Post-marketing reports have described hypersensitivity reactions, including angioedema. 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)

Rare cases of SCARs, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with pregabalin treatment. These reactions may be life-threatening or fatal. When initiating treatment with pregabalin, patients should be informed about the signs and symptoms of such reactions, and closely monitored for their occurrence. If signs or symptoms suggestive of these reactions appear, 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. Post-marketing reports have also described cases of loss of consciousness, confusion, and psychiatric disturbances. 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 treated with pregabalin compared to placebo; however, the incidence of fundus changes was higher in the placebo group (see section "Pharmacodynamics").

Post-marketing reports have also described ocular adverse reactions, including vision loss, blurred vision, or other changes in visual acuity, 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 by adding pregabalin, in order to switch to monotherapy with pregabalin.

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, diarrhea, flu-like syndrome, restlessness, depression, pain, seizures, hyperhidrosis, and dizziness, indicating physical dependence. This information should be communicated to patients prior to initiating therapy.

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

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

Heart failure

Post-marketing reports have described cases of congestive heart failure in some patients receiving 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

When treating central neuropathic pain due to spinal cord injury, the overall frequency of adverse reactions, particularly those affecting the central nervous system such as somnolence, increased. This may be related to 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 behavior

Cases of suicidal thoughts and behavior have been reported in patients receiving antiepileptic drugs for various indications. Meta-analysis of data from randomized, placebo-controlled trials of antiepileptic drugs showed a small increased risk of suicidal thoughts and behavior. Suicidal thoughts and behavior have also been reported in patients treated with pregabalin in the post-marketing period (see section "Adverse reactions"). An epidemiological study using a self-controlled case series design (comparing treatment periods with non-treatment periods within individuals) demonstrated an increased risk of new-onset suicidal behavior and suicide death in patients receiving pregabalin.

If signs of suicidal thoughts or behavior emerge, patients (and caregivers) should seek immediate medical help. Patients should be monitored for signs of suicidal ideation and behavior, and appropriate treatment considered. If suicidal thoughts or behavior occur, discontinuation of pregabalin therapy should be considered.

Worsening of lower gastrointestinal tract function

Post-marketing reports have described worsening of lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) with pregabalin use, particularly when co-administered with constipating agents such as opioid analgesics. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be implemented (especially 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 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 pregabalin doses (≤ 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 cause drug dependence, which may occur even at therapeutic doses. Cases of misuse and abuse have been reported. Patients with a history of substance abuse may be at higher risk of misuse, abuse, and dependence; therefore, pregabalin should be used with caution in such patients. The risk of misuse, abuse, or dependence should be carefully assessed before initiating pregabalin therapy.

Withdrawal symptoms

Withdrawal symptoms have been observed after discontinuation of short-term or long-term pregabalin therapy. Reported events include insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness. The emergence of withdrawal symptoms after stopping pregabalin may indicate drug dependence (see section "Adverse reactions"). This information should be communicated to patients before starting treatment.

If pregabalin therapy needs to be discontinued, it is recommended to taper gradually over at least 1 week, regardless of the indication (see section "Method of administration and dosage").

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

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

Encephalopathy

Cases of encephalopathy have been reported, primarily in patients with comorbid conditions that may predispose to encephalopathy.

Women of childbearing potential / Contraception

Pregabalin use during the first trimester of pregnancy may cause major congenital malformations in the fetus. Pregabalin should not be used during pregnancy except in cases of extreme necessity when the benefit to the pregnant woman clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment (see section "Use during pregnancy or breastfeeding").

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

Data from a Scandinavian observational study of over 2700 pregnancies exposed to pregabalin during the first trimester showed a higher prevalence of major congenital malformations (MCMs) in children (live or stillborn) born to mothers who took pregabalin compared to unexposed populations (5.9% vs. 4.1%).

The risk of MCMs in children whose mothers took pregabalin during the first trimester was slightly higher compared to children of unexposed mothers (adjusted prevalence ratio and 95% confidence interval: 1.14 [0.96–1.35]), as well as compared to children whose mothers took lamotrigine (1.29 [1.01–1.65]) or duloxetine (1.39 [1.07–1.82]).

Analysis of specific malformations showed increased risks for nervous system malformations, eye malformations, orofacial clefts, urinary system malformations, and genital organ malformations, although numbers were small and estimates imprecise.

Pregabalin should not be used during pregnancy except in cases of extreme necessity (i.e., 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 pregabalin use.

Fertility

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

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

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

Ability to affect reaction speed when driving or operating machinery.

Prеgabio® may have a slight or moderate influence on the ability to drive or operate machinery. Prеgabio® may cause dizziness and somnolence, thereby affecting 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 medicine Prigabio® is taken regardless of food intake.

This medicinal product is intended for oral use only.

Dosage.

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

Neuropathic pain.

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on individual response and tolerability, 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 individual response and 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 doses, may range between 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 individual response and tolerability, the dose may be increased to 300 mg per day after the first week of treatment. 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 medicine for the treatment of fibromyalgia is 300–450 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) over 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 per day dose, there is no evidence that this dose provides additional benefit; furthermore, this dose was associated with poorer tolerability. Considering dose-dependent adverse reactions, doses above 450 mg per day are not recommended. Since Prigabio® is primarily eliminated via the kidneys, dosage adjustment is required in patients with renal impairment.

Discontinuation of pregabalin.

According to current clinical practice, pregabalin therapy should be discontinued gradually over at least one week, regardless of the indication (see sections «Special instructions» and «Adverse reactions»).

Renal impairment.

Pregabalin is eliminated from systemic circulation in unchanged form, predominantly via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section «Pharmacokinetics»), dosage should be individually adjusted in patients with renal impairment as indicated in the table below, based on creatinine clearance (CLcr) calculated using the following formula:

Pregabalin is effectively removed from plasma by hemodialysis (50% of the drug is removed within 4 hours). For patients undergoing hemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, an additional dose of the medicine 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
Supplemental dose after hemodialysis (mg)
	25	100	Single dose+

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

• Additional dose means an extra single dose.

Hepatic impairment.

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

Elderly patients.

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

Children.

The safety and efficacy of pregabalin in children (under 18 years of age) have not been established. Currently available information is presented in the sections "Adverse reactions", "Pharmacodynamics" and "Pharmacokinetics", however, based on this information, no dosing recommendations can be provided for this patient population.

Overdose.

Since the drug has been marketed, the most commonly reported adverse reactions following pregabalin overdose have been somnolence, confusion, agitation and restlessness. Seizures have also been reported.

Coma has been reported rarely.

Management 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 development program for pregabalin, more than 8900 patients received the drug, including 5600 patients who participated in double-blind, placebo-controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally of mild or moderate severity. In all controlled trials, 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 (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

The reported 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 and especially somnolence (see section "Special precautions").

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

Table 2

System organ classes	Adverse reactions to pregabalin
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, difficulty in word finding, pathological dreams, increased libido, anorgasmia, apathy
Rare	Disinhibition, suicidal behaviour, suicidal thoughts
Frequency unknown	Drug dependence
Nervous system disorders
Very common	Dizziness, somnolence, headache
Common	Ataxia, coordination disorder, tremor, dysarthria, amnesia, memory impairment, attention disturbance, paresthesia, hypoaesthesia, sedation, balance disorder, lethargy
Uncommon	Syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, intentional tremor, nystagmus, cognitive disorder, mental disorder, speech disorders, hyporeflexia, hyperesthesia, burning sensation, augesia, 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	Visual loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcer, exophthalmos, extraocular muscle 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	QT interval prolongation, 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, hiccup, 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, hypoaesthesia of oral cavity, 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	Elevated 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 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, delayed ejaculation, 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 feelings, increased fatigue
Uncommon	Generalized edema, facial swelling, chest tightness, pain, warmth, thirst, chills, generalized weakness, malaise, abscess, lipohypertrophy, 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 drug withdrawal have been observed after discontinuation of short-term or long-term pregabalin therapy. Reported symptoms included insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, 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 pregabalin discontinuation after long-term use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

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; and two open-label safety studies of 1 year duration, n=54 and n=431) was similar to the profile observed in adult epilepsy studies. The most commonly reported adverse reactions 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 in the 14-day pregabalin therapy 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 medicinal product 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 suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging.

14 capsules in a blister; 1, 2, or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto /KRKA, d.d., Novo mesto.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.