Lugabalin: detailed information

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

Composition:

Active substance: pregabalin;

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

Excipients: pregelatinized starch, talc.

Pharmaceutical form. Capsules.

Main physicochemical properties:

75 mg capsules: size 4 capsules with a dark brown cap and white body, marked in black ink "PG" on the cap and "75" on the body, containing white or almost white powder;
150 mg capsules: size 2 capsules with a white cap and white body, marked in black ink "PG" on the cap and "150" on the body, containing white or almost white powder;
300 mg capsules: size 0 capsules with a dark brown cap and white body, marked in black ink "PG" on the cap and "300" on the body, containing white or almost white powder.

Pharmacotherapeutic group. Drugs acting on the nervous system. 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

Efficacy of pregabalin has been demonstrated in clinical studies for the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. The efficacy of the medicinal product has not been studied in other types of neuropathic pain. 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 of peripheral and central origin pain was observed after the first week and persisted 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 in 18% of patients in the placebo group. Among patients who experienced somnolence, the proportion of responders was 48% in the pregabalin group and 16% in the placebo group.

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

Epilepsy

Adjunctive therapy. Pregabalin was studied in three controlled clinical trials lasting 12 weeks with a twice-daily or three-times-daily dosing regimen. Overall safety and efficacy profiles for twice-daily and three-times-daily dosing regimens were similar. Reduction in seizure frequency was observed as early as the first week. Children. The efficacy and safety of pregabalin as adjunctive therapy in epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study involving patients aged 3 months to 16 years (n=65) with partial seizures were similar to those in adults. Results from a 12-week placebo-controlled study involving 295 children aged 4 to 16 years, a 14-day placebo-controlled study involving 175 children aged 1 month to less than 4 years, aimed at evaluating the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and a 1-year open-label safety study involving 54 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 "Method of administration and dosage", "Adverse reactions", and "Pharmacokinetics"). In the 12-week placebo-controlled study, children received pregabalin at 2.5 mg/kg/day (maximum 150 mg/day), pregabalin at 10 mg/kg/day (maximum 600 mg/day), or placebo. At least a 50% reduction in partial seizures from baseline was observed in 40.6% of patients receiving pregabalin at 10 mg/kg/day (p=0.0068 compared to placebo), 29.1% of patients receiving pregabalin at 2.5 mg/kg/day (p=0.26 compared to 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 end-of-treatment 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) were randomized to receive 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 (in patients with newly diagnosed disease). Pregabalin was studied in one controlled clinical trial lasting 56 weeks with a twice-daily dosing regimen. When pregabalin was used, equivalent efficacy compared to lamotrigine was not achieved, as assessed at 6 months using the endpoint of seizure freedom. Pregabalin and lamotrigine were equally safe and well tolerated.

Generalized anxiety disorder

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

Reduction in symptoms of generalized anxiety disorder according to the Hamilton Anxiety Rating Scale (HAM-A) was observed as early as week 1. In controlled clinical trials (lasting 4–8 weeks), a ≥50% improvement in the total HAM-A score from baseline to endpoint was observed in 52% of patients receiving pregabalin and in 38% of patients in the placebo group.

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

Fibromyalgia

The efficacy of pregabalin was established in one 14-week double-blind placebo-controlled multicenter trial (F1) and one 6-week randomized withdrawal trial (F2). These trials included patients diagnosed with fibromyalgia based on American College of Rheumatology criteria (widespread pain for at least 3 months and pain present in 11 or more of 18 specific tender points). The trials demonstrated reduction in pain on the visual analog scale. Additional improvement was demonstrated by patient global impression 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 common adverse reactions observed in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics

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

Absorption

Pregabalin is rapidly absorbed when administered on an empty stomach and reaches maximum plasma concentrations within 1 hour after single or multiple doses. The calculated oral bioavailability of pregabalin is ≥ 90% and is dose-independent. Steady state is achieved within 24–48 hours after multiple dosing. The rate of pregabalin absorption is reduced when taken 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 did not have a clinically significant effect on the extent of absorption.

Distribution

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

Metabolism

In humans, pregabalin undergoes minimal metabolism. After administration of a radiolabeled dose of pregabalin, approximately 98% of the radioactivity was excreted in urine as unchanged pregabalin. The fraction of the N-methylated metabolite of pregabalin – the main metabolite of the drug detected in urine – was 0.9% of the administered dose. Racemization of the S-enantiomer of pregabalin to the R-enantiomer did not occur during preclinical studies.

Elimination

Pregabalin is eliminated from systemic circulation in unchanged form, 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 "Renal impairment").

Dose adjustment of the medicinal product is required for patients with renal impairment or patients on hemodialysis (see section "Method of administration and dosage", table).

Linearity / non-linearity

The pharmacokinetics of pregabalin are linear over the entire recommended dose range. The variability of pregabalin pharmacokinetics among patients is low (< 20%). Pharmacokinetics after multiple dosing are predictable based on data obtained from single-dose administration. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.

Gender

Clinical study results indicate the absence of a 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 concentration of pregabalin decreases by approximately 50%). Since the drug is primarily eliminated by the kidneys, dose reduction is required for patients with renal impairment, and an additional dose should be administered after hemodialysis (see section "Method of administration and dosage", table).

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 dysfunction 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 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 and ranged from 0.5 to 2 hours after administration.

Cmax and area under the concentration-time curve (AUC) values of pregabalin increased linearly with increasing dose in each age group. In children with body weight less than 30 kg, AUC values were 30% lower, due to a 43% increase in body weight-adjusted clearance in these patients compared to patients with body weight ≥ 30 kg. The terminal elimination half-life of pregabalin averaged approximately 3–4 hours in children under 6 years of age and 4–6 hours in children aged 7 years and older.

Population pharmacokinetic analysis showed that creatinine clearance was a significant covariate for oral pregabalin clearance, and body weight was a significant covariate for 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 section "Method of administration and dosage", "Adverse reactions", and "Pharmacodynamics").

Elderly patients

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

Breastfeeding

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 passed 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 a dose of 300 mg/day or at the maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the mother's total daily dose normalized to mg/kg.

Clinical Characteristics

Indications

Neuropathic Pain

For the treatment of peripheral or central neuropathic pain in adults.

Epilepsy

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

Generalized Anxiety Disorder

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

Since pregabalin is predominantly excreted unchanged in urine, undergoes minimal metabolism in humans (less than 2% of the dose is excreted in urine as metabolites), does not inhibit in vitro metabolism of other agents, 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 showed that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate do not have a clinically significant effect on pregabalin clearance.

Oral Contraceptives, Norethisterone and/or Ethinylestradiol

Concomitant administration of pregabalin with oral contraceptives, norethisterone and/or ethinylestradiol does not affect the steady-state pharmacokinetics of either medicinal product.

Medicinal Products Affecting the CNS

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

Elderly Patients

No specific pharmacodynamic interaction studies have been conducted in elderly volunteers. 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 treatment with pregabalin may require adjustment of their antidiabetic medication.

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.

Serious skin reactions

Rare cases of serious skin adverse reactions (SSARs), 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.

Patients should be informed about the signs and symptoms of serious skin reactions, and skin reactions should be closely monitored during treatment. If signs or symptoms suggestive of such reactions occur, pregabalin should be discontinued immediately and alternative treatment considered (if necessary).

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

Pregabalin 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 loss of consciousness, confusion, and psychiatric disturbances. Therefore, patients should be advised to exercise caution until they are aware of how the medication affects them.

Visual disorders

During clinical trials, blurred vision was reported more frequently in patients receiving pregabalin compared to those receiving placebo. In most cases, this phenomenon resolved with continued treatment. Ophthalmological examinations revealed a higher incidence of decreased visual acuity and visual field changes in patients treated with pregabalin compared to placebo; however, the incidence of ocular fundus changes was higher in the placebo group.

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. Ocular symptoms may resolve or diminish after discontinuation of pregabalin.

Renal impairment

Cases of renal impairment have been reported. This effect was sometimes reversible after discontinuation of pregabalin.

Discontinuation of concomitant antiepileptic drugs

There is insufficient data to support switching to pregabalin monotherapy after achieving seizure control with adjunctive pregabalin treatment.

Withdrawal symptoms

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

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

Post-marketing reports have described cases of heart failure in some patients taking pregabalin. This reaction was most commonly observed during treatment of neuropathic pain in elderly patients with cardiovascular disorders. Pregabalin should be used with caution in such patients. This effect may resolve upon discontinuation of pregabalin.

Treatment of central neuropathic pain due to spinal cord injury

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

Respiratory depression

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

Suicidal thoughts and behaviour

Cases of suicidal thoughts and behaviour have been reported in patients receiving antiepileptic drugs for various indications.

A meta-analysis of randomized, placebo-controlled antiepileptic drug trials also showed a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is unknown. Post-marketing reports have described suicidal thoughts 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 in 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 help if signs of suicidal thoughts or behaviour emerge. Patients should be monitored for the emergence of suicidal thoughts and behaviour, and appropriate treatment should be considered. Discontinuation of pregabalin therapy should be considered if suicidal thoughts or behaviour occur.

Worsening of lower gastrointestinal tract function

Post-marketing reports have described events related to worsening of lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) following pregabalin use in combination with constipation-inducing medications 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

Concomitant use of pregabalin with opioids should be done with caution due to the risk of CNS depression. In a controlled study among opioid users, patients who received pregabalin together with an opioid had an increased risk of opioid-related mortality compared to those who used 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 greater risk at higher doses (> 300 mg, aOR 2.51 [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, abuse, and dependence have been reported. The drug should be used with caution in patients with a history of substance abuse. The risk of misuse, abuse, or dependence should be carefully assessed before prescribing pregabalin. Patients should be monitored for symptoms of misuse, abuse, or dependence (cases of tolerance, dose escalation, and drug-seeking behaviour have been reported).

Withdrawal symptoms

Withdrawal symptoms have been observed in some patients after discontinuation of short- or long-term pregabalin therapy. Reported events include insomnia, headache, nausea, anxiety, diarrhoea, flu-like symptoms, restlessness, depression, suicidal thoughts, pain, seizures, hyperhidrosis, and dizziness. 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 do so gradually over at least 1 week, regardless of the indication (see section "Dosage and administration").

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

There are no data on the frequency and severity of withdrawal symptoms related to the duration of pregabalin use or its dose in long-term treatment.

Encephalopathy

Cases of encephalopathy occurred predominantly in patients with concomitant conditions that may predispose to encephalopathy.

Women of childbearing potential / contraception

Pregabalin use during the first trimester of pregnancy may cause major congenital malformations in the unborn child. Pregabalin should not be used during pregnancy unless clearly necessary and 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").

Pregnancy and breastfeeding

Women of childbearing potential / contraception for women and men

Since the potential risk to humans is unknown, effective contraception should be used (see section "Special precautions for use").

Pregnancy

Animal studies have shown reproductive toxicity.

Pregabalin crosses the placenta in rats (see section "Pharmacokinetics"). Pregabalin may cross the human placenta.

Major congenital malformations

Data from an observational study conducted in Scandinavian countries, involving over 2700 pregnancies, showed a higher prevalence of major congenital malformations (MCMs) in children (live or stillborn) exposed to pregabalin during the first trimester compared to unexposed children (5.9% vs. 4.1%).

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

Analysis of specific malformations showed a higher risk of nervous system malformations, eye malformations, orofacial clefts, urinary tract malformations, and genital organ malformations, although the number of such cases was small and estimates imprecise. Pregabalin should not be used during pregnancy unless clearly necessary (when the benefit to the mother clearly outweighs the potential risk to the fetus).

Breastfeeding

A small amount of pregabalin has been detected in human breast milk. Women who are breastfeeding should be advised that breastfeeding is not recommended during treatment with pregabalin.

Fertility

There are no clinical data on the effect of pregabalin on female reproductive function. In a clinical study on the effect of pregabalin on sperm motility in healthy male participants, a dose of 600 mg per day was administered. After three months of treatment, no effect on sperm motility was observed. Fertility studies showed a negative effect on reproductive function in female animals and a negative effect on reproductive function and development in male rats. The clinical relevance of these findings is unknown.

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration

Doses

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

Neuropathic pain

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into two doses. Depending on efficacy and individual tolerability, the dose may be increased to 300 mg per day after an interval of 3 to 7 days, and if necessary, to the maximum dose of 600 mg per day after an additional 7-day interval.

Epilepsy

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into two 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 150–600 mg per day. The need for continued treatment should be periodically re-evaluated.

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. 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.

Fibromyalgia

The usual dose of pregabalin for most patients is 300–450 mg per day given in two divided doses. Some patients may require a dose of 600 mg per day. Treatment should be initiated at a dose of 75 mg twice daily (150 mg/day) and may be increased, depending on efficacy and tolerability, to 150 mg twice daily (300 mg/day) within one week. For patients in whom a dose of 300 mg/day is insufficiently effective, the dose may be increased to 225 mg twice daily (450 mg/day). Although a study of 600 mg per day has been conducted, 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 pregabalin is primarily eliminated by the kidneys, dosage adjustment is necessary in patients with renal impairment.

Discontinuation of pregabalin treatment

According to current clinical practice, if pregabalin treatment needs to be discontinued, it is recommended to do so gradually over at least one week, regardless of the indication (see sections "Special precautions for use" and "Adverse reactions").

Patients with renal impairment

Pregabalin is eliminated from systemic circulation in unchanged form primarily via renal excretion. Since pregabalin clearance is directly proportional to creatinine clearance, dose reduction in patients with impaired renal function should be individualized according to creatinine clearance (CLcr), as specified in Table 1 and calculated using the following formula:

CLcr (mL/min) =[	1.23 × (140 – age (years) × body weight (kg))	] (× 0.85 for women)
	plasma creatinine level (mmol/L)

Pregabalin is effectively removed from plasma by hemodialysis (50% of the drug over 4 hours). For patients undergoing hemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, a supplemental dose of the medicinal product should be administered immediately following each 4-hour hemodialysis procedure (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
Creatinine clearance (CLcr), (mL/min)	Initial dose (mg/day)	Maximum dose (mg/day)	Dosing regimen
≥ 60	150	600	Twice or three times daily
≥ 30 – < 60	75	300	Twice or three times daily
≥ 15 – < 30	25–50**	150	Once or twice daily
< 15	25**	75	Once daily
Additional dose after hemodialysis (mg)
	25**	100**	Single dose

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

** Administer pregabalin at the appropriate dosage.

Patients with hepatic impairment

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

Use in elderly patients (over 65 years of age)

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

Method of administration

The medication should be taken independently of food intake.

The medication is intended exclusively for oral administration.

Children

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

Overdose

Symptoms. 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. Management of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis (see section "Method of administration and dosage", table).

Adverse Reactions

In the clinical development program for pregabalin, over 8,900 patients were exposed to the drug, including 5,600 patients in double-blind, placebo-controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally mild to moderate in severity. In all controlled trials, the discontinuation rate due to adverse reactions was 12% among patients receiving pregabalin and 5% among those receiving placebo. The most common adverse reactions leading to discontinuation of study medication in the pregabalin group were dizziness and somnolence.

Table 2 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 of occurrence (very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), frequency not known (cannot be estimated from available data)). Within each frequency grouping, adverse reactions are listed in order of decreasing severity. The listed adverse reactions may also be related to the underlying disease and/or concomitant use of other medicinal products.

During treatment of central neuropathic pain due to spinal cord injury, the overall incidence of adverse reactions, CNS-related adverse reactions, and particularly somnolence, was increased (see section "Special Warnings and Precautions for Use"). Additional adverse reactions reported after marketing authorization are presented in italics.

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: decreased 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 alterations, depersonalization, word-finding difficulty, abnormal dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition, suicidal behaviour, suicidal ideation.

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, sedative effect, balance disorder, lethargy.

Uncommon: syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, postural dizziness, intention tremor, nystagmus, cognitive dysfunction, psychiatric disorders, speech disorders, hyporeflexia, hyperesthesia, burning sensation, ageusia, malaise, apathy, perioral paresthesia, myoclonus.

Rare: seizures, parosmia, hypokinesia, dysphagia, parkinsonism, hypalgesia, dependence, cerebellar syndrome, cogwheel rigidity, coma, delirium, encephalopathy, extrapyramidal disorder, Guillain-Barré syndrome, intracranial hypertension, manic reactions, paranoid reactions, sleep disorders.

Eye Disorders

Common: blurred vision, diplopia, conjunctivitis.

Uncommon: peripheral vision loss, visual disturbance, eye swelling, visual field defects, decreased visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, blepharitis, accommodation disorder, eye hemorrhage, photophobia, retinal edema.

Rare: vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulcer, exophthalmos, oculomotor paralysis, iritis, keratoconjunctivitis, miosis, night blindness, ophthalmoplegia, optic nerve atrophy, optic disc edema, ptosis, uveitis.

Ear and Labyrinth Disorders

Common: vertigo.

Uncommon: hyperacusis.

Cardiac Disorders

Uncommon: tachycardia, first-degree atrioventricular block, sinus bradycardia, congestive heart failure.

Rare: prolonged QT interval, sinus tachycardia, sinus arrhythmia.

Vascular Disorders

Uncommon: arterial hypotension, arterial hypertension, flushing, hyperemia, cold sensation in extremities.

Respiratory, Thoracic and Mediastinal Disorders

Common: pharyngolaryngeal pain.

Uncommon: dyspnea, epistaxis, cough, nasal congestion, rhinitis, snoring, dryness of nasal mucosa.

Rare: pulmonary edema, throat tightness, laryngospasm, apnea, atelectasis, bronchiolitis, hiccups, pulmonary fibrosis, yawning.

Frequency not known: respiratory depression.

Gastrointestinal Disorders

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

Uncommon: gastroesophageal reflux disease, hypersalivation, oral hypoaesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, tongue swelling, rectal bleeding.

Rare: ascites, pancreatitis, tongue swelling, dysphagia, aphthous stomatitis, esophageal ulcer, periodontal abscess.

Hepatobiliary Disorders

Uncommon: increased hepatic enzymes*.

Rare: jaundice.

Very rare: hepatic 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 (TEN), 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, 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, fatigue.

Uncommon: generalized edema, facial swelling, chest tightness, pain, hot flushes, thirst, chills, malaise, weakness, abscess, lipodermatitis, photosensitivity reactions.

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

Investigations

Common: weight increased.

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

Rare: decreased blood leukocyte count.

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

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

There are no data on the frequency and severity of withdrawal symptoms associated with the duration of pregabalin use and dosage following long-term treatment discontinuation (see sections "Dosage and Administration", "Special Warnings and Precautions for Use").

Paediatric population. The safety profile of pregabalin established in three studies involving paediatric patients with partial seizures with or without secondary generalization (a 12-week efficacy and safety study in patients with partial seizures, n=295; a pharmacokinetic and tolerability study, n=65; and a 1-year open-label safety study, n=54) was similar to that observed in adult epilepsy studies. 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 (see sections "Dosage and Administration", "Pharmacodynamics", and "Pharmacokinetics").

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf Life

2 years.

Storage Conditions

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

Keep out of reach of children.

Packaging

75 mg capsules: 14 capsules in a blister, 2 or 4 blisters in a cardboard box;

150 mg capsules: 14 capsules in a blister, 4 blisters in a cardboard box;

300 mg capsules: 14 capsules in a blister, 2 blisters in a cardboard box.

Prescription Status

Prescription only.

Manufacturer

Lupin Limited.

Manufacturer's Address and Place of Business

PLOT NO. 15 B, PHASE 1A, VAPI INDUSTRIAL AREA, VAPI, TALUKA – VALSAD, DISTRICT – VAPI, GUJARAT – 396195, INDIA.

Marketing Authorization Holder

Sky Pharma VZ LLC.

Address of Marketing Authorization Holder

Unit No. 708S, 7th Floor, Dubai Science Park (DSP), South Tower, Dubai Science Park, Dubai, United Arab Emirates.