Lyrica

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

Composition:

Active substance: pregabalin;

1 capsule contains 50 mg, 75 mg, 150 mg, or 300 mg of pregabalin;

Excipients: lactose monohydrate; corn starch; talc; capsule shell: gelatin, water, titanium dioxide (E 171), sodium lauryl sulfate, anhydrous colloidal silicon dioxide, iron oxide red (E 172) (for 75 mg and 300 mg capsules); printing inks: shellac, iron oxide black (E 172), propylene glycol, potassium hydroxide.

Pharmaceutical form. Capsules.

Main physicochemical properties.

• 50 mg capsules: hard, opaque (white/white) gelatin capsules with a black band, size 3, containing a white or almost white powder. Markings on the body: "PGN 50", on the cap: "Pfizer" in black ink.
• 75 mg capsules: hard, opaque (white/orange) gelatin capsules, size 4, containing a white or almost white powder. Markings on the body: "PGN 75", on the cap: "Pfizer" in black ink.
• 150 mg capsules: hard, opaque (white/white) gelatin capsules, size 2, containing a white or almost white powder. Markings on the body: "PGN 150", on the cap: "Pfizer" in black ink.
• 300 mg capsules: hard, opaque (white/orange) gelatin capsules, size 0, containing a white or almost white powder. Markings on the body: "PGN 300", on the cap: "Pfizer" in black ink.

Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs.

ATC code N03AX16.

Pharmacological properties.

Pharmacodynamics.

The active substance is pregabalin, which is a gamma-aminobutyric acid analogue [(S)-3-(aminomethyl)-5-methylhexanoic acid].

Mechanism of action.

Pregabalin binds to the auxiliary subunit (α2–δ protein) of voltage-dependent calcium channels in the central nervous system (CNS).

Clinical efficacy and safety.

• Neuropathic pain.

Efficacy of the medicinal product for the treatment of diabetic neuropathy, postherpetic neuralgia, and spinal cord injury has been demonstrated in clinical studies. The efficacy of pregabalin in other types of neuropathic pain has not been studied.

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

In clinical trials of up to 12 weeks duration 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 of 12 weeks duration with twice-daily or three-times-daily dosing regimens. Overall, the 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 including patients aged from 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, designed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for partial seizures, and two open-label safety studies of 1 year duration involving 54 and 431 children 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", "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 less than 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, for pregabalin at 7 mg/kg/day, 5.4 and 1.4 for pregabalin at 14 mg/kg/day, and 2.9 and 2.3 for placebo. Pregabalin at 14 mg/kg/day significantly reduced the logarithmically transformed frequency of partial seizures compared to placebo (p = 0.0223); pregabalin at 7 mg/kg/day did not demonstrate improvement compared to placebo.

In a 12-week placebo-controlled study of patients with primary generalized tonic-clonic (PGTC) seizures, 219 patients aged 5 to 65 years (including 66 patients aged 5 to 16 years) received pregabalin at 5 mg/kg/day (maximum 300 mg/day) or 10 mg/kg/day (maximum 600 mg/day) or placebo as adjunctive therapy. At least a 50 % reduction in PGTC seizure frequency was observed in 41.3 %, 38.9 %, and 41.7 % of patients receiving pregabalin at 5 mg/kg/day, pregabalin at 10 mg/kg/day, and placebo, respectively.

Monotherapy (in patients with newly diagnosed disease). Pregabalin was studied in one controlled clinical trial of 56 weeks duration with a twice-daily dosing regimen. When pregabalin was used, equivalent efficacy compared to lamotrigine was not achieved, based on assessment at 6 months using the primary endpoint of seizure-free status. Pregabalin and lamotrigine were equally safe and well tolerated.

• Generalized anxiety disorder.

Pregabalin was studied in 6 controlled trials of 4–6 weeks duration, 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 (4–8 weeks duration), improvement of at least 50 % in total HAM-A score from baseline to endpoint was observed in 52 % of patients receiving pregabalin and 38 % of patients in the placebo group.

During controlled trials, blurred vision was observed more frequently in patients receiving pregabalin than in those receiving placebo. In most cases, this phenomenon 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 patients 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 patients in the placebo group. Fundus changes were detected in 1.7 % of patients receiving pregabalin and 2.1 % in the placebo group.

• Fibromyalgia.

The efficacy of Lyrica has been established in one 14-week double-blind placebo-controlled multicenter trial (F1) and one 6-week randomized withdrawal trial (F2). Patients enrolled in these trials had a diagnosis of fibromyalgia based on American College of Rheumatology criteria (widespread pain for at least 3 months and pain in 11 or more of 18 specific tender points). The trials demonstrated 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 Lyrica at doses of 75–450 mg/day. Based on the primary efficacy endpoint (change in overall pain intensity from baseline to week 15, measured on an 11-point rating scale), numerically greater improvement was observed in patients receiving pregabalin compared to those receiving placebo, but this improvement did not reach statistical significance. The most commonly observed adverse reactions in clinical trials were dizziness, nausea, headache, weight gain, and fatigue. The overall safety profile in adolescents was similar to that in adults with fibromyalgia.

Pharmacokinetics.

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

Absorption.

Pregabalin is rapidly absorbed when administered on an empty stomach and reaches maximum plasma concentrations within 1 hour after single or multiple doses. The calculated oral bioavailability of pregabalin is ≥ 90 % and is dose-independent. At steady state, achieved within 24–48 hours with multiple dosing. 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 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 in 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 derivative of pregabalin—the main metabolite 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.

Excretion.

Pregabalin is excreted unchanged from systemic circulation, primarily via the kidneys. The mean elimination half-life of pregabalin is 6.3 hours. Plasma and renal clearance of pregabalin are directly proportional to creatinine clearance (see section "Pharmacokinetics. Renal impairment").

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

Linearity/non-linearity.

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

Gender.

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

Renal impairment.

Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (after 4 hours of hemodialysis, plasma concentration of pregabalin decreases by approximately 50 %). Since the drug is primarily excreted 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).

Hepatic impairment.

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

Children.

The pharmacokinetics of pregabalin were evaluated in children with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years, and 12 to 16 years) receiving doses of 2.5 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, time to maximum plasma concentration was generally similar across all age groups, ranging from 0.5 to 2 hours after administration.

Cmax and area under the concentration-time curve (AUC) values of pregabalin increased linearly with dose in each age group. In children with body weight 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.

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 sections "Posology and method of administration", "Adverse reactions", and "Pharmacodynamics").

Elderly patients.

Pregabalin clearance tends to decrease with age. This decrease in pregabalin clearance with oral administration is consistent with the age-related decrease 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).

Lactation.

The pharmacokinetics of pregabalin administered at a dose of 150 mg every 12 hours (daily dose 300 mg) were evaluated in 10 breastfeeding women at least 12 weeks postpartum. Breastfeeding did not affect or had minimal effect on the pharmacokinetics of pregabalin. Pregabalin was excreted into breast milk, with average steady-state concentrations in breast milk being approximately 76 % of maternal plasma concentrations. The calculated infant dose received via breast milk (assuming average milk consumption of 150 mL/kg/day) from a woman taking pregabalin at a dose of 300 mg/day or the maximum dose of 600 mg/day is 0.31 or 0.62 mg/kg/day, respectively. These calculated doses represent approximately 7 % of the maternal daily dose normalized to mg/kg.

Clinical characteristics.

Indications.

Neuropathic pain.

Lyrica is indicated for the treatment of peripheral or central neuropathic pain in adults.

Epilepsy.

Lyrica is indicated in adults as adjunctive therapy for partial seizures with or without secondary generalization.

Generalized anxiety disorder.

Lyrica is 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 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 may cause or be subject to pharmacokinetic interactions.

In vivo studies and population pharmacokinetic analysis.

Thus, clinically significant pharmacokinetic interactions between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol were not observed in in vivo studies. Population pharmacokinetic analysis demonstrated that oral antidiabetic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate have no clinically significant effect on pregabalin clearance.

Oral contraceptives, norethisterone and/or ethinylestradiol.

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

Medicinal products affecting the CNS.

Pregabalin may potentiate the effects of ethanol and lorazepam. 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 impairments caused by oxycodone.

Interactions in elderly patients.

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

Special precautions for use.

Patients with diabetes mellitus.

According to current clinical practice, some patients with diabetes mellitus who experience weight gain during pregabalin therapy may require adjustment of their antidiabetic medication doses.

Hypersensitivity reactions.

Post-marketing reports have described hypersensitivity reactions, including angioedema. If symptoms of angioedema such as facial swelling, perioral swelling, or upper airway swelling occur, pregabalin should be discontinued immediately.

Serious skin reactions (SSRs)

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

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

Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of 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 clinical trials, blurred vision was reported 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 upon discontinuation of pregabalin, have been reported.

Discontinuation of concomitant antiepileptic drugs.

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

Heart failure.

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

Treatment of central neuropathic pain due to spinal cord injury.

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

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, and elderly patients may be at increased risk of this serious adverse reaction. Dose adjustments may be required for these patients.

Suicidal thoughts and behavior.

Cases of suicidal thoughts and behavior have been reported in patients receiving antiepileptic drugs for various indications. 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 in 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 emerge. Patients should be monitored for the emergence of suicidal thoughts and behavior, and appropriate treatment should be considered. If suicidal thoughts or behavior occur, discontinuation of pregabalin therapy should be considered.

Worsening of lower gastrointestinal tract function.

Post-marketing reports have described 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. When pregabalin is used concomitantly with opioids, measures to prevent 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 of opioid users, an increased risk of opioid-related mortality was observed in patients receiving pregabalin concomitantly with an opioid compared to those receiving opioids alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19–2.36]). This increased risk was observed at low pregabalin doses (≤ 300 mg, aOR 1.52 [95% CI, 1.04–2.22]), with a trend toward increased risk at higher pregabalin doses (> 300 mg, aOR 2.55 [95% CI 1.24–5.06]).

Abuse, misuse, or dependence.

Pregabalin may cause drug dependence, which can occur even at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance abuse may be at higher risk of pregabalin misuse, abuse, and dependence; therefore, pregabalin should be used with caution in such patients. A careful assessment of the risk of misuse, abuse, or dependence should be conducted 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 symptoms, restlessness, depression, pain, seizures, hyperhidrosis, and dizziness, indicating potential drug dependence. The emergence of withdrawal symptoms after discontinuation of pregabalin may indicate drug dependence (see section "Adverse reactions"). This information should be communicated to patients before initiating 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 "Dosage and administration").

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

Data on withdrawal 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, occurring predominantly in patients with comorbid conditions that may predispose to encephalopathy.

Women of childbearing potential / contraception.

Use of pregabalin during the first trimester of pregnancy may cause major congenital malformations in the fetus. Pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment (see section "Use during pregnancy or breastfeeding").

Lactose intolerance.

Lyrica contains lactose. This medicinal product should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Sodium content.

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

Use during pregnancy or breastfeeding.

Women of childbearing potential / contraceptive methods for women.

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

Pregnancy.

Reproductive toxicity has been demonstrated in animal studies.

Pregabalin has been shown to cross the placenta in rats (see section "Pharmacokinetics"). Pregabalin may cross the human placenta.

Major congenital malformations.

Observational data from a Scandinavian study involving over 2700 pregnancies showed a higher prevalence of major congenital malformations (MCMs) in the pediatric population (live-born or stillborn children) exposed to pregabalin during the first trimester compared to the unexposed population (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 malformations, although the number of such cases was small and estimates imprecise.

Lyrica should not be used during pregnancy unless clearly necessary (when benefit to the mother clearly outweighs the potential risk to the fetus).

Breastfeeding.

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

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.

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

Ability to influence reaction speed when driving or operating machinery.

Lyrica may have a slight or moderate influence on the ability to drive and operate machinery. Lyrica may cause dizziness and somnolence and thus may affect the ability to drive and operate machinery. Therefore, patients should be advised to refrain from driving, operating complex machinery, and 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.

Lyrica should be taken independently of food intake.

This medicinal product is intended for oral use only.

Dosage.

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

Neuropathic pain.

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on individual response and tolerability, the dose may be increased to 300 mg per day after 3–7 days, and if necessary, to the maximum dose of 600 mg per day after another 7 days.

Epilepsy.

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

Generalized anxiety disorder.

The dose, divided into 2 or 3 doses, may range between 150–600 mg per day. The need for continued 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. Following 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 ranges from 300 to 450 mg per day. Treatment should be initiated at a dose of 75 mg twice daily (150 mg per day). Depending on efficacy and tolerability, the dose may be increased to 150 mg twice daily (300 mg per day) within one week. For patients 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 evaluating a dose 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 exceeding 450 mg per day are not recommended. Since Lyrica is primarily eliminated via the kidneys, dosage adjustment is required in patients with renal impairment.

Discontinuation of pregabalin.

According to current clinical practice, pregabalin therapy should be discontinued gradually over at least one week, regardless of the indication (see sections “Special precautions” 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 renal impairment as indicated in the table below, based on creatinine clearance (CLcr) calculated using the following formula:

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

Dosage adjustment of pregabalin according to renal function.

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

• Additional dose means an extra single dose.

Hepatic impairment.

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

Geriatric patients.

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

Children.

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

Overdose.

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

Coma has been reported rarely.

Management of pregabalin overdose consists of general supportive measures and, if necessary, hemodialysis (see section "Dosage and administration", table).

Adverse Reactions

In the clinical development program of pregabalin, over 8900 patients received the drug, including 5600 participants 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 those receiving placebo. The most common adverse reactions leading to discontinuation of study medication in the pregabalin group 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 based on available data). Within each frequency group, adverse effects are listed in order of decreasing severity.

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

During treatment of central neuropathic pain due to spinal cord injury, the overall frequency of adverse reactions increased, particularly CNS-related adverse reactions and especially somnolence (see section "Special 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: loss of appetite, hypoglycemia.

Psychiatric disorders.

Common: euphoric mood, confusion, irritability, disorientation, insomnia, decreased libido.

Uncommon: hallucinations, panic attacks, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood alterations, depersonalization, difficulty finding words, 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, paraesthesia, hypoaesthesia, sedative effect, balance disorder, lethargy.

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

Rare: convulsions, parosmia, hypokinesia, dysphagia, parkinsonism, hypalgesia, dependence, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal syndrome, 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 haemorrhage, photophobia, retinal edema.

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

Ear and labyrinth disorders.

Common: vertigo.

Uncommon: hyperacusis.

Cardiac disorders.

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

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 haemorrhage, melena, tongue swelling, rectal bleeding.

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

Hepatobiliary disorders.

Uncommon: increased liver 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, 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, haematuria, 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, leucorrhea, 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, warmth, thirst, chills, general weakness, malaise, 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).

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

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

Children. The safety profile of pregabalin established in five studies involving pediatric patients with partial seizures with or without secondary generalization (a 12-week efficacy and safety study in patients aged 4 to 16 years, n=295; a 14-day efficacy and safety study in patients aged 1 month to less than 4 years, n=175; a pharmacokinetic and tolerability study, n=65; and two open-label, one-year safety studies, n=54 and n=431) was similar to that observed in adult epilepsy studies. The most commonly reported 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 reported 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 drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of the reach of children.

Packaging.

For 75 mg and 150 mg capsules – 14 or 21 capsules in a blister, 1 or 4 blisters in a cardboard box.

For 50 mg and 300 mg capsules – 21 capsules in a blister, 1 or 4 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Pfizer Manufacturing Deutschland GmbH.

Manufacturer's location and address of place of business.

Mooswaldallee 1, 79090 Freiburg Im Breisgau, Germany.