Pegasate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PEGASET

Composition:

Active substance: pregabalin;

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

Excipients: maize starch, talc;

capsule shell: iron oxide red (E 172) (for 75 mg and 300 mg strengths), titanium dioxide (E 171), gelatin, purified water, sodium lauryl sulfate, black printing ink (shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, concentrated ammonia solution, iron oxide black (E 172), potassium hydroxide, purified water).

Pharmaceutical form. Capsules.

Main physicochemical properties:

75 mg capsules: hard gelatin capsules size "4" with orange cap and white body, marked with black ink "Z" on the cap and "12" on the body, containing granular powder of white or almost white color;

150 mg capsules: hard gelatin capsules size "2" with white cap and white body, marked with black ink "Z" on the cap and "14" on the body, containing granular powder of white or almost white color;

300 mg capsules: gelatin capsules size "0" with orange cap and white body, marked with black ink "Z" on the cap and "17" on the body, containing granular powder of white or almost white color.

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

Pharmacological Properties

Pharmacodynamics

The active substance of the medicinal product is pregabalin — an 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

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 for 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, the safety and efficacy profiles of the twice-daily and three-times-daily regimens were similar.

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

In controlled clinical trials of peripheral neuropathic pain, 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 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 central neuropathic pain, 22% of patients receiving pregabalin and 7% of patients receiving placebo experienced a 50% improvement on the pain rating scale.

• Epilepsy

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

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

Children. The efficacy and safety of pregabalin as an adjunctive treatment for epilepsy in children under 12 years of age and adolescents have not been established. Adverse reactions observed in a pharmacokinetic and tolerability study 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 and a 14-day placebo-controlled study involving 175 children aged 1 month to <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 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 "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 from baseline was observed in 40.6% of patients receiving pregabalin at 10 mg/kg/day (p = 0.0068 vs. placebo), 29.1% of patients receiving pregabalin at 2.5 mg/kg/day (p = 0.2600 vs. placebo), and 22.6% of those receiving placebo.

In the 14-day placebo-controlled study, children (aged 1 month to <4 years) received pregabalin at 7 mg/kg/day, pregabalin at 14 mg/kg/day, or placebo. Median daily seizure frequency at baseline and at the final visit was 4.7 and 3.8, respectively, with pregabalin at 7 mg/kg/day; 5.4 and 1.4 with pregabalin at 14 mg/kg/day; and 2.9 and 2.3 in the placebo group. 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), 10 mg/kg/day (maximum 600 mg/day), or placebo as adjunctive therapy. At least a 50% reduction in PGTC seizure frequency was observed in 41.3%, 38.9%, and 41.7% of patients receiving pregabalin at 5 mg/kg/day, pregabalin at 10 mg/kg/day, and placebo, respectively.

Monotherapy (for patients with newly diagnosed disease). Pregabalin was studied in one controlled clinical trial lasting 56 weeks with a twice-daily dosing regimen. Pregabalin did not achieve equivalent efficacy compared to lamotrigine, as assessed at 6 months using the primary endpoint 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 trial with a double-blind relapse prevention phase lasting 6 months.

Reduction in symptoms of generalized anxiety disorder on the Hamilton Anxiety Rating Scale (HAM-A) was observed as early as the first week.

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 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 fundus examination with dilated pupils) were performed in over 3600 patients in controlled clinical trials. Among these patients, visual acuity worsened in 6.5% of those in the pregabalin group and 4.8% in the placebo group. Visual field changes were detected in 12.4% of patients receiving pregabalin and 11.7% of those in the placebo group. Fundus changes were observed in 1.7% of patients receiving pregabalin and 2.1% 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 lasting at least 3 months and pain present in at least 11 of 18 specific tender points). The trials demonstrated a 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 adolescents 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 concentrations are 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% reduction in maximum concentration (Cmax) and an increase in tmax to approximately 2.5 hours. However, co-administration of pregabalin with food did not have a clinically significant effect on the extent of absorption.

Distribution

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

Metabolism

In humans, pregabalin undergoes 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 — accounted for 0.9% of the administered dose. During preclinical studies, no racemization of the S-enantiomer of pregabalin to the R-enantiomer occurred.

Elimination

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 subsection "Renal impairment" below).

Dose adjustment of the medicinal product is required for patients with renal impairment or patients on hemodialysis (see Table 1 in the section "Dosage and administration").

Linearity/Non-linearity

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

Gender

Clinical trial 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. Additionally, 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 necessary for patients with renal impairment, and an additional dose should be administered after hemodialysis (see Table 1 in the section "Dosage and administration").

Hepatic impairment

Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes minimal metabolism and is primarily excreted unchanged in urine, it is unlikely that hepatic 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, ranging from 0.5 to 2 hours after dosing. Cmax and area under the concentration-time curve (AUC) values of pregabalin increased linearly with dose in each age group. In children with body weight below 30 kg, AUC values were 30% lower, due to a 43% 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 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.

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 (aged 65 years and older)

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

Breastfeeding

The pharmacokinetics of pregabalin were evaluated in 10 breastfeeding women who were at least 12 weeks postpartum, receiving a dose of 150 mg every 12 hours (daily dose 300 mg). Lactation had no effect or only a minor effect on the pharmacokinetics of pregabalin. Pregabalin was excreted into breast milk, with average steady-state concentrations in breast milk being approximately 76% of maternal plasma concentrations. The calculated infant dose received via breast milk (assuming average milk intake of 150 mL/kg/day) from a woman taking pregabalin at 300 mg/day or the maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7% of the total daily dose received by the mother, normalized to body weight.

Clinical characteristics

Indications

Neuropathic pain. Pegasel capsules are indicated for the treatment of peripheral or central neuropathic pain in adults.

Epilepsy. Pegasel capsules are indicated in adults as adjunctive therapy in partial seizures, with or without secondary generalization.

Generalized anxiety disorder. Pegasel capsules are indicated for the treatment of generalized anxiety disorder in adults.

Fibromyalgia.

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 excreted in urine predominantly in unchanged form, 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 the drug may cause pharmacokinetic interactions or be a target of such 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 demonstrated that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate have no clinically significant effect on pregabalin clearance.

Oral contraceptives norethisterone and/or ethinylestradiol.

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

Medicinal products affecting the CNS

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

Interactions in elderly patients.

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

Special precautions for use

Patients with diabetes

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

Hypersensitivity reactions

Post-marketing reports have described the development of 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 skin adverse reactions

Rare cases of severe skin adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be life-threatening or fatal, have been reported during treatment with pregabalin. Patients should be informed about possible manifestations of these reactions, and skin condition should be closely monitored during pregabalin therapy. If signs or symptoms suggestive of severe skin reactions occur, pregabalin should be discontinued immediately and alternative treatment considered (if necessary).

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

Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of accidental injury (e.g., falls) in elderly patients. 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 studies, 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 trials 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 ocular 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 after discontinuation of pregabalin, have been reported.

Discontinuation of concomitant antiepileptic drugs

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

Heart failure

Post-marketing reports have described cases of 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

During treatment of 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 treatment of this condition. This should be taken into account when prescribing pregabalin for this indication.

Respiratory depression

Cases of severe respiratory depression associated with pregabalin use have been reported. 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. Such patients may require dose adjustment.

Suicidal thoughts and behavior

Cases of suicidal thoughts and behavior have been reported in patients receiving antiepileptic drugs for various indications. A meta-analysis of data 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.

Post-marketing reports have described cases of suicidal thoughts and behavior in patients receiving pregabalin (see section "Adverse reactions"). An epidemiological study using a self-controlled design (comparing treatment periods with non-treatment periods within individual patients) demonstrated an increased risk of new-onset suicidal behavior and fatal outcomes due to suicide in patients receiving pregabalin.

Patients (and caregivers) should seek medical help if signs of suicidal thoughts or behavior occur. In such cases, close monitoring of the patient should be ensured and appropriate treatment considered. If suicidal thoughts or behavior occur, discontinuation of pregabalin therapy should also be considered.

Worsening of lower gastrointestinal tract function

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

Concomitant use with opioids

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 taking opioids, the risk of opioid-related death was higher in patients receiving pregabalin concomitantly with an opioid compared to those taking opioids alone (adjusted odds ratio [aOR] 1.68; 95% confidence interval [CI] 1.19–2.36). This increased risk was observed with 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 2.51; 95% CI 1.24–5.06).

Improper use, abuse, or dependence

Pregabalin may cause drug dependence, which may occur even at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance abuse are at higher risk of misuse, abuse, and dependence, and pregabalin should be used with caution in such patients. 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 in some patients after discontinuation of short-term or long-term pregabalin therapy. Reported symptoms include insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, restlessness, depression, pain, seizures, hyperhidrosis, dizziness, and suicidal thoughts, indicating potential drug dependence. The occurrence of withdrawal symptoms after stopping pregabalin may indicate drug dependence (see section "Adverse reactions"). This information should be communicated to patients before starting therapy.

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

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

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

Encephalopathy

Cases of encephalopathy have been reported with pregabalin use, occurring primarily 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 unless 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 lactation").

Sodium content

The medicinal product contains less than 1 mmol sodium (23 mg) per capsule, i.e., practically sodium-free. This information may be provided to patients on a low-sodium diet.

Use during pregnancy or lactation

Women of childbearing potential / contraception

Since the potential risk to humans is unknown, women of childbearing potential must use effective contraception during treatment with pregabalin.

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.

An observational study conducted in Scandinavian countries, which followed over 2700 pregnancies, found that pregabalin use during the first trimester was associated with a higher prevalence of major congenital malformations (MCMs) in children (live or stillborn) exposed to pregabalin 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 unexposed children (adjusted prevalence ratio 1.14; 95% CI: 0.96–1.35) and compared to children exposed to lamotrigine (adjusted prevalence ratio 1.29; 95% CI: 1.01–1.65) or duloxetine (adjusted prevalence ratio 1.39; 95% CI: 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 malformations was small and estimates imprecise.

The medicinal product Pegasect should not be used during pregnancy without strong medical justification (when benefit to the mother clearly outweighs the potential risk to the fetus).

Lactation

A small amount of pregabalin has been detected in human breast milk. Women 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 rats, adverse effects on reproductive function in females and on reproductive function and development in males were observed. The clinical significance 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 thereby affect the ability to drive and operate machinery. Therefore, patients should be advised to refrain from driving, operating complex machinery, or other potentially hazardous activities until they know how this medicinal product affects their ability to perform such activities.

Method of Administration and Dosage

Method of Administration

The medicinal product Pegasert should be administered orally only; it can be taken independently of food intake.

Dosage

The dosage range is from 150 to 600 mg per day in 2 or 3 divided 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 of treatment.

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

A dose of 150 to 600 mg per day, administered in 2 or 3 divided doses, is used. The need for continued therapy 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. After an additional week, the dose may be increased to the maximum of 600 mg per day.

Fibromyalgia

The recommended dose of the drug for the treatment of fibromyalgia is 300 to 450 mg per day. Treatment should be initiated with a dose of 75 mg twice daily (150 mg per day). Depending on efficacy and tolerability, the dose may be increased to 150 mg twice daily (300 mg per day) within one week. For patients in whom a dose of 300 mg per day is insufficiently effective, the dose may be increased to 225 mg twice daily (450 mg per day). Although a study has evaluated the use of a 600 mg per day dose, there is no evidence that this dose provides additional benefit; moreover, it was less well tolerated. Due to dose-dependent adverse reactions, doses exceeding 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

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

Renal Impairment

Pregabalin is eliminated from systemic circulation in unchanged form, primarily via the kidneys. Since pregabalin clearance is directly proportional to creatinine clearance (see section "Pharmacokinetics"), dosage should be individually adjusted in patients with impaired renal function as indicated in Table 1, based on creatinine clearance (CLcr) calculated using the following formula:

Pregabalin is effectively removed from plasma by hemodialysis (50% of the drug within 4 hours). For patients undergoing hemodialysis, the daily dose of pregabalin should be adjusted according to renal function. In addition to the daily dose, an extra dose of the drug should be administered immediately after each 4-hour hemodialysis session (see Table 1).

Table 1. Dose 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 in patients with impaired liver function (see section "Pharmacokinetics").

Elderly patients

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

Children

The safety and efficacy of pregabalin in children (under 18 years of age) have not been established. Available information is presented in the section "Adverse reactions" and in sections "Pharmacodynamics" and "Pharmacokinetics", but it is insufficient to provide dosing recommendations for this patient group.

Overdose

Following marketing of the drug, the most commonly reported adverse reactions in cases of pregabalin overdose were somnolence, confusion, agitation, and restlessness. Seizures have also been observed.

Coma has been reported rarely.

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

Adverse Reactions

In the clinical development program for pregabalin, more than 8900 patients received the drug, including 5600 participants 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 pregabalin were dizziness and somnolence.

Below are listed 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 (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse effects are listed in order of decreasing severity.

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

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

Additional adverse reactions reported after marketing of the drug are listed below and indicated 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 swings, depersonalization, word-finding difficulty, pathological dreams, increased libido, anorgasmia, apathy.

Rare: disinhibition, suicidal behaviour, suicidal ideation.

Frequency not known: drug dependence.

Nervous system disorders

Very common: dizziness, somnolence, headache.

Common: ataxia, coordination disorder, tremor, dysarthria, amnesia, memory impairment, attention disturbance, paresthesia, hypesthesia, sedation, balance disorder, lethargy.

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

Rare: convulsions, 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, 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, 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 hemorrhage.

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

Hepatobiliary disorders

Uncommon: increased liver enzymes (alanine aminotransferase and aspartate aminotransferase).

Rare: jaundice.

Very rare: liver failure, hepatitis.

Skin and subcutaneous tissue disorders

Common: pressure ulcers.

Uncommon: papular rash, urticaria, hyperhidrosis, itching, alopecia, dry skin, eczema, hirsutism, skin ulcers, vesiculobullous rash.

Rare: 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 spasms, arthralgia, back pain, limb pain, neck muscle spasms.

Uncommon: joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness.

Rare: rhabdomyolysis.

Renal and urinary disorders

Uncommon: urinary incontinence, dysuria, albuminuria, hematuria, kidney stone formation, nephritis.

Rare: renal failure, oliguria, urinary retention, acute renal failure, glomerulonephritis, pyelonephritis.

Reproductive system and breast disorders

Common: erectile dysfunction, impotence.

Uncommon: sexual dysfunction, ejaculation delay, dysmenorrhea, breast pain, leukorrhea, menorrhagia, metrorrhagia.

Rare: amenorrhea, galactorrhea, breast enlargement, gynecomastia, cervicitis, balanitis, epididymitis.

General disorders and administration site conditions

Common: peripheral edema, edema, gait disturbance, falls, feeling drunk, unusual feelings, increased fatigue.

Uncommon: generalized edema, facial swelling, chest tightness, pain, heat sensation, thirst, chills, general weakness, malaise, abscess, lipodermatitis, photosensitivity reactions.

Rare: granuloma, self-injury, 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 white blood cell count.

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

Data on discontinuation of long-term pregabalin treatment indicate that the frequency and severity of withdrawal symptoms may be dose-dependent.

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 <4 years, n = 175; a pharmacokinetic and tolerability study, n = 65; two open-label, 1-year safety studies, n = 54 and n = 431) was similar to that observed in studies in adult patients with epilepsy. The most commonly observed adverse events in the 12-week pregabalin treatment study were somnolence, pyrexia, upper respiratory tract infections, increased appetite, weight gain, and nasopharyngitis. The most commonly observed adverse events in the 14-day pregabalin treatment study were somnolence, upper respiratory tract infections, and pyrexia (see sections "Dosage and Administration", "Pharmacodynamics", and "Pharmacokinetics").

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

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

Packaging. 28 capsules: 7 capsules per blister; 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Aurobindo Pharma Limited - Unit VII.

Manufacturer's address and location of operations

Special Economic Zone, TSIIC, Plot No. S1, Sy. No. 411/R, 425/R, 434/R, 435/R and 458/R, Green Industrial Park, Polepalli Village, Jeedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India.