Pagamax

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PAGAMAX (PAGAMAX)

Composition:

Active substance: pregabalin;

1 capsule contains 75 mg of pregabalin;

Excipients: lactose monohydrate, corn starch, talc, colloidal anhydrous silicon dioxide; hard gelatin capsule No. 4*;

* composition of the gelatin capsule: titanium dioxide (E 171), iron oxide red (E 172), gelatin;

1 capsule contains 150 mg of pregabalin;

Excipients: lactose monohydrate, corn starch, talc, colloidal anhydrous silicon dioxide; hard gelatin capsule No. 2*;

* composition of the gelatin capsule: titanium dioxide (E 171), gelatin;

1 capsule contains 300 mg of pregabalin;

Excipients: lactose monohydrate, corn starch, talc, colloidal anhydrous silicon dioxide; hard gelatin capsule No. 0*;

* composition of the gelatin capsule: titanium dioxide (E 171), iron oxide red (E 172), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties:

75 mg capsules: hard gelatin capsule with a white body and an orange cap, marked with black "75" on the body. The capsule contents: white powder;

150 mg capsules: hard gelatin capsule with white cap and body, marked with black "150" on the body. The capsule contents: white powder;

300 mg capsules: hard gelatin capsule with a white body and an orange cap, marked with black "300" on the body. The capsule contents: white powder.

Pharmacotherapeutic group.

Antiepileptic agents. ATC code N03A X16.

Pharmacological Properties

Pharmacodynamics

Active substance – pregabalin, which is a gamma-aminobutyric acid analogue

((S)-3-(aminomethyl)-5-methylhexanoic acid).

Pregabalin binds to the auxiliary subunit (α2-δ protein) of voltage-dependent calcium channels in the central nervous system and potently displaces [3H]-gabapentin in experimental settings.

Neuropathic Pain

The efficacy of the drug has been demonstrated in clinical studies on diabetic neuropathy, postherpetic neuralgia, and spinal cord injury. Efficacy in other types of neuropathic pain has not been studied.

Safety and efficacy profiles for dosing regimens of 2–3 times daily were similar.

Pain reduction was observed during the first week and maintained throughout the treatment period.

Epilepsy

Adjunctive therapy. Pregabalin was studied in three controlled clinical trials lasting 12 weeks with dosing regimens twice or three times daily. Overall, safety and efficacy profiles for twice- and three-times-daily regimens were similar. Reduction in seizure frequency was observed as early as the first week.

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), 52% of patients treated with pregabalin and 38% of patients in the placebo group showed improvement of at least 50% in total HAM-A score from baseline to endpoint.

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 decreased in 6.5% of patients in the pregabalin group and in 4.8% in the placebo group. Visual field changes were observed in 12.4% of patients receiving pregabalin and in 11.7% of placebo group patients. Fundus changes were detected in 1.7% of patients receiving pregabalin and in 2.1% of patients in the placebo group.

Pharmacokinetics

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

Absorption. Pregabalin is rapidly absorbed after oral administration on an empty stomach and reaches maximum plasma concentration within 1 hour after single and multiple doses. The calculated oral bioavailability of pregabalin is 90% or higher and is dose-independent. Steady-state concentrations are achieved within 24–48 hours after repeated administration. The extent of pregabalin absorption is reduced when taken with food, resulting in a decrease of approximately 25–30% in maximum concentration (Cmax) and an increase of approximately 2.5 hours in time to reach maximum concentration (tmax). However, co-administration with food did not have a clinically significant effect on the overall extent of absorption.

Distribution. The apparent volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin does not bind to plasma proteins.

Metabolism. Pregabalin undergoes minimal metabolism. After administration of a radiolabeled dose of pregabalin, approximately 98% of radioactivity is excreted in urine as unchanged drug. The N-methylated derivative of pregabalin (the main metabolite detectable in urine) accounted for 0.9% of the administered dose. Studies have shown no racemization of the S-enantiomer to the R-enantiomer.

Elimination. Pregabalin is removed from systemic circulation primarily by renal excretion in unchanged form. The mean elimination half-life of pregabalin is 6.3 hours. Plasma and renal clearance of pregabalin are directly proportional to creatinine clearance. Dose adjustment is required for patients with renal impairment or those undergoing hemodialysis.

Linearity/Non-linearity. The pharmacokinetics of pregabalin are linear over the entire recommended dose range. Inter-subject pharmacokinetic variability for pregabalin is low (less than 20%). The pharmacokinetics of multiple doses are predictable based on single-dose data. Therefore, routine monitoring of plasma concentrations of pregabalin is not required.

Pharmacokinetics in Specific Patient Populations

Gender. There is no 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 concentrations of pregabalin decrease by approximately 50%). Since renal excretion is the main elimination pathway of the drug, dose reduction is necessary for patients with renal impairment, and an additional dose should be administered after hemodialysis.

Hepatic Impairment. Specific pharmacokinetic studies in patients with hepatic impairment have not been conducted. Since pregabalin undergoes negligible metabolism and is primarily excreted unchanged in urine, it is unlikely that hepatic impairment would affect plasma concentrations of pregabalin.

Elderly Patients (over 65 years of age). Pregabalin clearance tends to decrease with age. This reduction in oral pregabalin clearance is consistent with the age-related decline in creatinine clearance. Dose reduction of pregabalin may be required for elderly patients with age-related renal impairment.

Clinical characteristics.

Indications.

Neuropathic pain.

Treatment of neuropathic pain in adults due to damage of the peripheral and central nervous systems.

Epilepsy.

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

Generalized anxiety disorder.

Treatment of generalized anxiety disorder in adults.

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 drugs, 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 agent.

Medicinal products affecting the CNS.

Pregabalin may potentiate the effects of ethanol and lorazepam. During post-marketing surveillance, cases of respiratory depression, coma, and fatal outcomes have been reported in patients taking pregabalin concomitantly with opioids and/or other centrally acting medicinal products. Pregabalin is likely to enhance cognitive and gross motor impairment caused by oxycodone.

Interaction in elderly patients.

No specific pharmacodynamic interaction studies have been conducted in elderly volunteers. Interaction studies have been performed only in adults.

Special precautions for use.

Patients with diabetes mellitus.

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

Hypersensitivity reactions.

Hypersensitivity reactions, including angioedema, have been reported. If symptoms of angioedema such as facial swelling, perioral swelling, or swelling of the upper airways occur, pregabalin should be discontinued immediately.

Severe skin reactions.

Rare cases of severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with pregabalin treatment, which may be life-threatening or fatal. When prescribing the medicinal product, patients should be informed about the signs and symptoms, and skin reactions should be closely monitored. If signs or symptoms suggestive of these reactions occur, pregabalin should be discontinued immediately and alternative treatment considered (if necessary).

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

Pregabalin use has been associated with dizziness and somnolence, which may increase the risk of traumatic events (falls) in elderly patients. Loss of consciousness, confusion, and psychiatric disturbances have also been reported. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of the medicinal product.

Visual disorders.

During clinical trials, blurred vision was reported more frequently among patients receiving pregabalin compared to those receiving placebo. In most cases, this phenomenon resolved with continued treatment. In 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.

Adverse reactions affecting the eye, including vision loss, blurred vision, or other changes in visual acuity, have been reported, many of which were transient. Symptoms related to the visual system may decrease or resolve after discontinuation of pregabalin.

Renal impairment.

Cases of renal impairment have been reported. In some instances, this effect was reversible after discontinuation of pregabalin.

Discontinuation of concomitant antiepileptic drugs.

There is insufficient data regarding the discontinuation of concomitant antiepileptic drugs after seizure control has been achieved with the addition of pregabalin to allow transition to pregabalin monotherapy.

Withdrawal symptoms.

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, restlessness, depression, pain, seizures, hyperhidrosis, and dizziness. This information should be communicated to patients prior to initiating treatment.

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

There are no data on the frequency and severity of withdrawal symptoms associated with duration of pregabalin use and dosage when discontinuing long-term treatment.

Heart failure.

Cases of congestive heart failure have been reported in some patients taking pregabalin. This reaction was mostly observed during pregabalin treatment for neuropathic pain in elderly patients with 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 incidence of adverse reactions, particularly those affecting the central nervous system (especially somnolence), was increased. This may be related to the additive effect of concomitant medications (e.g., antispastic agents) required for managing this condition. This factor should be considered when prescribing pregabalin to such patients.

Respiratory depression.

Cases of severe respiratory depression have been reported in association with pregabalin use. Patients with impaired respiratory function, respiratory or neurological disorders, renal impairment, concomitant use of CNS depressants, and elderly individuals may be at higher risk of this serious adverse reaction. Dose adjustment 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 randomized, placebo-controlled antiepileptic drug trials also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown. Post-marketing reports have documented 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 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 worsening of lower gastrointestinal tract function (such as intestinal obstruction, paralytic ileus, constipation) associated with pregabalin use in combination with medications that may cause constipation, such as opioid analgesics. When pregabalin is used concomitantly with opioids, preventive measures for constipation should be implemented (particularly 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 together with an opioid compared to those receiving opioids alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19–2.36]). This increased risk was observed at low pregabalin doses (≤ 300 mg, aOR 1.52 [95% CI, 1.04–2.22]), with a trend toward higher risk at high pregabalin doses (> 300 mg, aOR 2.55 [95% CI, 1.24–5.06]).

Misuse, abuse, or dependence.

Cases of misuse, abuse, and dependence have been reported. The drug should be used with caution in patients with a history of substance abuse; patients should be monitored for symptoms of misuse, abuse, or dependence on pregabalin (cases of addiction, dose escalation, and drug-seeking behavior have been reported).

Encephalopathy.

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

Lactose intolerance.

The product contains lactose monohydrate. Patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception for women and men.

Since the potential risk in humans is unknown, women of childbearing potential should use effective contraception.

Pregnancy.

There are no reliable data on the use of pregabalin during pregnancy.

Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

Pagamax should not be used during pregnancy except in exceptional cases where the benefit to the pregnant woman clearly outweighs the potential risk to the fetus.

Breastfeeding.

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

Reproductive function.

There are no clinical data on the effect of pregabalin on female fertility.

In a clinical study assessing the effect of pregabalin on sperm motility in healthy male volunteers receiving 600 mg pregabalin daily, no effect on sperm motility was observed after three months of treatment.

Effect on ability to drive and use machines.

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

Administration and Dosage

For oral use.

Doses

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

Neuropathic pain

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on efficacy and individual patient tolerability, the dose may be increased to 300 mg per day after an interval of 3 to 7 days, and if necessary, further increased to the maximum dose of 600 mg per day after an additional seven-day interval.

Epilepsy

Treatment with pregabalin may be initiated at a dose of 150 mg per day, divided into 2 or 3 doses. Depending on efficacy and tolerability in the individual patient, 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 to 600 mg per day. The need for continued treatment should be periodically reassessed.

Treatment with pregabalin may be initiated at a dose of 150 mg per day. Depending on efficacy and tolerability in individual patients, the dose may be increased to 300 mg per day after the first week of treatment. After another week of treatment, the dose may be increased to 450 mg per day. Following an additional week, the dose may be increased to the maximum of 600 mg per day.

Discontinuation of pregabalin treatment

According to current clinical practice, pregabalin treatment should be discontinued gradually over a period of at least one week, regardless of the indication.

Patients with renal impairment

Pregabalin is eliminated from systemic circulation unchanged, predominantly via renal excretion. Since pregabalin clearance is directly proportional to creatinine clearance (CrCl), dosage reduction in patients with impaired renal function should be individualized according to creatinine clearance (CrCl), as indicated in the table below and calculated using the formula:

CrCl (mL/min) =

Pregabalin is effectively removed from plasma by hemodialysis (approximately 50% of the drug is eliminated 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, a supplemental dose of the drug should be administered immediately after each 4-hour hemodialysis session (see table).

Dosage adjustment of pregabalin according to renal function

Creatinine clearance (CLcr), (mL/min)	Total daily dose of pregabalin *		Dosing regimen
	Initial dose (mg/day)	Maximum dose (mg/day)
≥ 60	150	600	2-3 times daily
≥ 30–< 60	75	300	2-3 times daily
≥ 15–< 30	25-50	150	1-2 times 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 dose per administration (mg/dose).

Patients with hepatic impairment.

Dose adjustment is not required for patients with hepatic impairment.

Use in elderly patients (over 65 years of age).

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

The drug should be taken independently of food intake.

Children.

The safety and efficacy of pregabalin in children (under 18 years of age) have not been established.

Overdose.

The most common adverse reactions in case of pregabalin overdose were somnolence, confusion, agitation, and restlessness. Seizures have also been reported.

Coma has been reported rarely.

Treatment of pregabalin overdose consists of general supportive measures and, if necessary, may include hemodialysis.

Adverse Reactions

The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were generally mild or moderate in intensity.

The adverse reactions listed below are categorized by organ systems 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).

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

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, agitation, restlessness, depression, depressed mood, mood alterations, depersonalization, difficulty in word finding, pathological dreams, increased libido, anorgasmia, apathy, elevated mood, aggression.

Rare: disinhibition, suicidal behaviour, suicidal ideation.

Nervous system disorders:

Very common: dizziness, somnolence, headache.

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

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

Rare: convulsions, parosmia, hypokinesia, hypalgesia, dependence, mania, cerebellar syndrome, cogwheel syndrome, coma, delirium, encephalopathy, extrapyramidal disorder, Guillain–Barré syndrome, intracranial hypertension, manic reaction, paranoid reaction, sleep disorder, loss of consciousness, hypalgesia, dysgraphia, parkinsonism.

Eye disorders:

Common: blurred vision, diplopia, conjunctivitis.

Uncommon: peripheral vision loss, visual disturbance, eye swelling, visual field defect, reduced visual acuity, eye pain, asthenopia, photopsia, dry eyes, increased lacrimation, eye irritation, accommodation disorder, blepharitis, subconjunctival haemorrhage, photophobia, retinal edema.

Rare: vision loss, keratitis, oscillopsia, altered depth perception, mydriasis, strabismus, visual brightness, anisocoria, corneal ulceration, 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: 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, excessive salivation, oral hypoaesthesia, cholecystitis, cholelithiasis, colitis, gastrointestinal hemorrhage, melena, tongue swelling, rectal bleeding.

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

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: 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, toxic epidermal necrolysis (TEN).

Musculoskeletal and connective tissue disorders:

Common: muscle cramps, arthralgia, back pain, limb pain, neck spasms.

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

Rare: rhabdomyolysis.

Renal and urinary disorders:

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

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

Reproductive system and breast disorders:

Common: erectile dysfunction, impotence.

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

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

General disorders and administration site conditions:

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

Uncommon: generalized edema, facial swelling, chest tightness, pain, heat sensation, thirst, increased body temperature, malaise, general weakness, abscess, cellulitis, photosensitivity reactions.

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

Investigations:

Common: weight increased.

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

* 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, influenza-like symptoms, convulsions, restlessness, depression, suicidal ideation, pain, hyperhidrosis, and dizziness, which suggest physical dependence. This information should be communicated to the patient prior to initiating therapy.

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

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Shelf life. 2 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

14 capsules in a blister pack, 1 or 4 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of operations.

Sankaklar District, Eskikarakoca Avenue, No: 299, 81100 Duzce, Turkey.