Pregabalin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PREGABALIN (PREGABALIN)

Composition:

Active substance: pregabalin;

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

Excipients: pregelatinized starch, purified talc; hard gelatin capsule (gelatin, iron oxide red (E172) (for 75 mg and 300 mg capsules), titanium dioxide (E171)); black printing ink (shellac, anhydrous alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, concentrated ammonia solution, iron oxide black (E172), potassium hydroxide, water).

Pharmaceutical form. Capsules.

Main physicochemical properties:

75 mg capsules: hard gelatin capsules of size 4 with an orange cap and a white body, printed with "SG" on the cap and "75" on the body in black ink; capsule contents – white or almost white powder;

150 mg capsules: hard gelatin capsules of size 2 with a white cap and a white body, printed with "SG" on the cap and "150" on the body in black ink; capsule contents – white or almost white powder;

300 mg capsules: hard gelatin capsules of size 0 with an orange cap and a white body, printed with "SG" on the cap and "300" on the body in black ink; capsule contents – white or almost white powder.

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

Pharmacological Properties

Pharmacodynamics

Active substance — pregabalin, 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 diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. 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 twice-daily dosing regimen and in trials lasting up to 8 weeks with a three-times-daily regimen. Overall, safety and efficacy profiles for twice-daily and three-times-daily dosing regimens were similar.

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

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

In a controlled clinical trial of central neuropathic pain, a 50% improvement on the pain rating scale was observed in 22% of patients receiving pregabalin and 7% of patients receiving placebo.

Epilepsy

Adjunctive therapy

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

Reduction in seizure frequency was observed as early as the first week.

Paediatric population

The efficacy and safety of pregabalin as 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 4 years, aimed at evaluating 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 "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% in the placebo group.

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 mean 24-hour 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 involving 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), pregabalin at 10 mg/kg/day (maximum 600 mg/day), or placebo as adjunctive therapy. At least a 50% reduction in the frequency of PGTC seizures 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, based on the 6-month endpoint assessment of 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 relapse prevention study 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), improvement of at least 50% 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.

In controlled trials, blurred vision occurred more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this adverse event resolved with continued therapy. Ophthalmological examinations (including visual acuity testing, formal visual field testing, and fundus examination with dilated pupils) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity was reduced in 6.5% of patients in the pregabalin group and 4.8% in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and 11.7% of patients in the placebo group. Fundus changes were observed in 1.7% of patients receiving pregabalin and 2.1% of patients in the placebo group.

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 oral bioavailability of pregabalin is estimated to be ≥ 90% and is dose-independent. After repeated dosing, steady state is achieved within

24–48 hours. The rate of pregabalin absorption is reduced when administered with food, resulting in approximately a 25–30% decrease in maximum concentration (Cmax) and prolongation of tmax to approximately 2.5 hours. However, administration of pregabalin with food does not have a clinically significant effect on the extent of its 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 recovered in urine as unchanged drug. The fraction of the N-methylated derivative of pregabalin—the main metabolite of pregabalin detected in urine—was 0.9% of the administered dose. Preclinical studies showed no evidence of racemization of the S-enantiomer of pregabalin to the

R-enantiomer.

Elimination

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

Dose adjustment is required for patients with renal impairment or patients on hemodialysis (see section "Posology and method of administration", Table 1).

Linearity / non-linearity

The pharmacokinetics of pregabalin are linear within the recommended daily dose range. Inter-subject variability in pregabalin pharmacokinetics is low (< 20%). Pharmacokinetics after multiple dosing can be predicted from single-dose data. Therefore, routine monitoring of plasma pregabalin concentrations is not necessary.

Gender

Clinical study results indicate that gender does not have a clinically significant effect 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, dose reduction is required for patients with renal impairment, and supplemental dosing is required after hemodialysis (see section "Posology and method of administration", Table 1).

Hepatic impairment

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is excreted in urine predominantly in unchanged form, it is unlikely that hepatic impairment would significantly alter plasma concentrations of pregabalin.

Paediatric population

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, the time to reach maximum plasma concentration was generally similar across all age groups, ranging from 0.5 to 2 hours after dose administration.

Cmax and AUC parameters 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% increase in body weight-adjusted clearance in these patients compared to patients with body weight ≥ 30 kg.

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

Population pharmacokinetic analysis showed that creatinine clearance was a significant covariate of oral clearance of pregabalin, and body weight was a significant covariate of the apparent volume of distribution of 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 "Posology and method of administration", "Undesirable effects", and "Pharmacodynamics").

Elderly patients

Pregabalin clearance tends to decrease with age. This reduction in oral pregabalin clearance is consistent with age-related reduction in creatinine clearance. Elderly patients with age-related renal impairment may require dose reduction of pregabalin (see section "Posology and method of administration", Table 1).

Breast-feeding period

Pregabalin pharmacokinetics after administration at a dose of 150 mg every 12 hours (daily dose 300 mg) were evaluated in 10 breastfeeding women at least 12 weeks postpartum. Lactation had practically no effect on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk with a mean steady-state concentration 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 mother 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 peripheral and central neuropathic pain in adults.

Epilepsy

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

Generalized Anxiety Disorder

Treatment of generalized anxiety disorder in adults.

Contraindications

Hypersensitivity to pregabalin or to any of the excipients of the medicinal product.

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 the 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

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 has shown that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate have no clinically significant effect on pregabalin clearance.

Oral Contraceptives, Norethisterone, and Ethinylestradiol

Concomitant administration of pregabalin with oral contraceptives, norethisterone, and ethinylestradiol does not affect the steady-state pharmacokinetics of any of these substances.

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 fatal outcomes have been reported in patients who took pregabalin together with opioids and/or other medicinal products that suppress CNS function. Pregabalin is likely to enhance cognitive and gross motor function impairment caused by oxycodone.

Interactions in Elderly Patients

No specific pharmacodynamic interaction studies have been conducted in elderly volunteers. Drug interaction studies have been performed only in adult patients.

Special precautions for use

Patients with diabetes mellitus

According to current clinical practice, some diabetic patients whose body weight has increased during pregabalin therapy may require adjustment of antidiabetic medication doses.

Hypersensitivity reactions

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

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which may be life-threatening or fatal, have been rarely reported during treatment with pregabalin. Patients should be informed of these signs and symptoms, and skin reactions should be closely monitored. 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 cognitive disturbances

Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of accidental injuries (falls) in elderly patients. Cases of loss of consciousness, confusion, and cognitive disturbances have also 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 was observed 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 the placebo group; 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 have also been reported, including vision loss, blurred vision, or other changes in visual acuity, many of which were transient. Discontinuation of pregabalin may help resolve or reduce these symptoms.

Renal impairment

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

Discontinuation of concomitant antiepileptic drugs

There is currently insufficient data on the possibility of discontinuing concomitant antiepileptic drugs after seizure control has been achieved with the addition of pregabalin to allow transition to pregabalin monotherapy.

Congestive heart failure

Congestive heart failure has been reported in the post-marketing period in some patients taking pregabalin. These reactions were mostly observed in elderly patients with pre-existing cardiovascular disorders during treatment of neuropathic pain. Pregabalin should be used with caution in such patients. This condition may resolve after 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 incidence of adverse reactions, particularly those affecting the central nervous system such as somnolence, increased. This may be related to the additive effect of concomitant medications (e.g., antispastic agents) required for the management of 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, those receiving concomitant CNS depressants, and elderly patients are at higher risk of this serious adverse reaction. Dose adjustments may be required for these patients (see section "Dosage and administration").

Suicidal thoughts and behavior

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

Patients (or caregivers) should be advised to seek medical help if signs of suicidal thoughts or behavior occur. Patients should be closely monitored for signs of suicidal ideation and behavior, and the need for appropriate treatment should be considered. If suicidal thoughts or behavior occur, pregabalin should be discontinued.

Worsening of lower gastrointestinal tract function

In the post-marketing period, events related to worsening of lower gastrointestinal tract function (such as 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. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be taken (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 among individuals using opioids, an increased risk of opioid-related mortality was observed in patients receiving pregabalin concomitantly with an opioid compared to those using opioids alone (adjusted odds ratio [aOR] 1.68 [95% CI (confidence interval) 1.19–2.36]). This increased risk was observed at low doses of pregabalin (≤ 300 mg, aOR 1.52 [95% CI 1.04–2.22]) with a trend toward increased risk at higher doses (> 300 mg, aOR 2.55 [95% CI 1.24–5.06]).

Misuse, abuse, or dependence

Use of pregabalin at therapeutic doses may lead to drug dependence. Cases of abuse and misuse of the drug have been reported. Patients with a history of substance abuse have a higher risk of misuse, abuse, or dependence on pregabalin and should therefore be treated with caution. The risk of misuse, abuse, or dependence should be carefully assessed before prescribing pregabalin.

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

Withdrawal symptoms

Withdrawal symptoms have been observed after discontinuation of short-term or long-term pregabalin use. Reported symptoms include insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness. The occurrence of withdrawal symptoms after discontinuation of pregabalin may indicate drug dependence (see section "Adverse reactions"). Patients should be informed of this prior to initiation of treatment.

If pregabalin use needs to be discontinued, it is recommended to do so gradually over at least 1 week, regardless of the indication (see section "Dosage and administration").

Seizures, including epileptic status and generalized tonic-clonic 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 depend on the dose.

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 fetus. Pregabalin should not be used during pregnancy except when 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 or breastfeeding").

Use during pregnancy or breastfeeding

Women of childbearing potential / contraception

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

Pregnancy

Animal studies indicate reproductive toxicity of pregabalin.

Pregabalin has been shown to cross the placenta in rats. Pregabalin may cross the human placenta.

Major congenital malformations

According to data from an observational study conducted in Scandinavian countries, which followed more than 2700 pregnancies exposed to pregabalin during the first trimester, the prevalence of major congenital malformations (MCMs) among children (liveborn or stillborn) exposed to pregabalin was higher compared to those not exposed (5.9% vs. 4.1%).

The risk of MCMs in children whose mothers used pregabalin during the first trimester of pregnancy was slightly higher compared to children not exposed in utero [adjusted prevalence ratio and 95% CI: 1.14 (0.96–1.35)], as well as compared to children exposed to lamotrigine [1.29 (1.01–1.65)] or duloxetine [1.39 (1.07–1.82)].

Analysis by specific malformations showed a higher risk of malformations of the nervous system, eyes, orofacial clefts, urinary tract, and genital organs; however, the number of such malformations was 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 human breast milk (see section "Pharmacokinetics"). The effect of pregabalin on neonates/infants is unknown. During breastfeeding, a decision should 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 mother.

Fertility

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

In a clinical study assessing 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.

Fertility studies in female rats showed adverse effects on reproductive function. Fertility studies in male rats showed adverse effects on reproductive function and development. The clinical significance of these findings is unknown.

Ability to affect reaction speed when driving vehicles or operating machinery

Pregabalin may have a slight or moderate influence on the ability to drive vehicles or operate machinery. Pregabalin may cause dizziness and somnolence and thus may impair the ability to drive vehicles or operate machinery. Patients should refrain from driving vehicles, 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

For oral use.

The medicinal product can be taken independently of food intake.

Dosage

The dosage range of the medicinal product may vary between 150–600 mg per day, 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 further increased to the maximum of 600 mg per day.

Generalized Anxiety Disorder

The dosage range is 150 to 600 mg per day, divided into 2 or 3 doses. The need for continued treatment should be periodically reviewed.

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. Following an additional week, the dose may be increased to the maximum of 600 mg per day.

Discontinuation of Pregabalin

According to current clinical practice, pregabalin therapy should be discontinued gradually over a period of at least one week, regardless of the indication (see sections "Special Warnings and Precautions for Use" 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"), the dose should be individually adjusted in patients with renal impairment according to creatinine clearance (CLcr), as indicated in Table 1 below, calculated using the 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 additional 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

Creatinine clearance (CLcr) (mL/min)	Total daily dose of pregabalin*		Dosing regimen
	Initial dose (mg/day)	Maximum dose (mg/day)
≥ 60	150	600	Two or three times daily
≥ 30 – < 60	75	300	Two 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 according to the dosing regimen to obtain the single dose (mg/dose).

**Additional dose — a single additional dose.

Hepatic impairment

Dose adjustment is not required for patients with impaired liver function (see section "Pharmacokinetics").

Geriatric patients

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

Children

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

Overdose

As reported in the post-marketing period, the most commonly reported symptoms 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

The clinical development program for pregabalin included over 8900 patients, of whom more than 5600 participated in double-blind, placebo-controlled studies. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally of mild or moderate severity. In all controlled studies, the discontinuation rate due to adverse reactions was 12% among patients receiving pregabalin and 5% among patients receiving placebo. The most common adverse reactions leading to discontinuation of pregabalin were dizziness and somnolence.

Table 2 below lists 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 category, adverse reactions are listed in order of decreasing severity.

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

In the treatment of central neuropathic pain due to spinal cord injury, the overall frequency of adverse reactions, the frequency of CNS-related adverse reactions, and particularly somnolence were increased (see section "Special precautions").

Additional adverse reactions reported during the post-marketing period are indicated in italics.

Table 2

Organs and organ systems	Frequency	Adverse reaction
Infections and infestations	Common	nasopharyngitis
Blood and lymphatic system	Uncommon	neutropenia
Immune system	Uncommon	hypersensitivity
	Rare	angioedema, allergic reactions
Metabolism and nutrition	Common	increased appetite
	Uncommon	anorexia, hypoglycemia
Psychiatric disorders	Common	euphoric mood, confusion, irritability, disorientation, insomnia, decreased libido
	Uncommon	hallucination, panic attacks, restlessness, excitement, depression, depressed mood, elevated mood, aggression, mood swings, depersonalization, difficulty finding words, unusual dreams, increased libido, anorgasmia, apathy
	Rare	disinhibition, suicidal behavior, suicidal thoughts
	Unknown	drug dependence
Nervous system	Very common	dizziness, somnolence, headache
	Common	ataxia, coordination disorder, tremor, dysarthria, amnesia, memory impairment, attention disturbance, paresthesia, hypesthesia, sedative effect, balance disorder, lethargy
	Uncommon	syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive disorders, psychiatric disorders, speech disorders, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise
	Rare	seizures, parosmia, hypokinesia, dysgraphia, parkinsonism
Eye disorders	Common	blurred vision, diplopia
	Uncommon	peripheral vision loss, visual disturbance, eye swelling, visual field defect, reduced visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation
	Rare	vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness
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, hypertension, flushing, hyperemia, cold sensation in extremities
Respiratory, thoracic and mediastinal disorders	Uncommon	dyspnea, epistaxis, cough, nasal congestion, rhinitis, snoring, dry nose
	Rare	pulmonary edema, sensation of throat tightness
	Unknown	respiratory depression
Gastrointestinal disorders	Common	vomiting, nausea, constipation, diarrhea, flatulence, abdominal distension, dry mouth
	Uncommon	gastroesophageal reflux disease, increased salivation, oral cavity hypesthesia
	Rare	ascites, pancreatitis, tongue swelling, dysphagia
Hepatobiliary disorders	Uncommon	elevated liver enzymes*
	Rare	jaundice
	Very rare	hepatic failure, hepatitis
Skin and subcutaneous tissue disorders	Uncommon	papular rash, urticaria, hyperhidrosis, pruritus
	Rare	toxic epidermal necrolysis, Stevens-Johnson syndrome, cold sweat
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 rigidity
	Rare	rhabdomyolysis
Renal and urinary disorders	Uncommon	urinary incontinence, dysuria
	Rare	renal failure, oliguria, urinary retention
Reproductive system and breast disorders	Common	erectile dysfunction (impotence)
	Uncommon	sexual dysfunction, ejaculation delayed, dysmenorrhea, breast pain
	Rare	amenorrhea, breast discharge, breast enlargement, gynecomastia
General disorders and administration site reactions	Common	peripheral edema, edema, gait disturbance, falls, feeling drunk, unusual feeling, fatigue
	Uncommon	generalized edema, facial swelling, chest tightness, pain, fever, thirst, chills, asthenia
Investigations	Common	weight increased
	Uncommon	increased blood creatine phosphokinase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, decreased body weight
	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. Patients should be informed about this prior to initiation of therapy.

Data on pregabalin discontinuation after prolonged use suggest that the frequency and severity of withdrawal symptoms may be dose-dependent (see sections “Dosage and Administration” and “Special Warnings”).

Pediatric population

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 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 studies in adult patients with epilepsy. The most commonly reported 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 reported adverse reactions 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 of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children, in the original packaging, at a temperature not exceeding 25 °C.

Packaging. 10 capsules in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer

Steril-Djen Life Sciences (P) Ltd.

Manufacturer's address and location of business operations

No. 45, Mangalam Main Road, Villianur Commune, Puducherry, 605110, India.