Gabantin 300

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Gabantin 300 (Gabantin 300)

Composition:

Active substance: gabapentin;

1 capsule contains 300 mg of gabapentin, calculated as 100% anhydrous substance;

Excipients: microcrystalline cellulose, corn starch, talc;

Capsule shell composition: gelatin, titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules, white in color. The contents of the capsules – a white or almost white powder; presence of compacted columns or lumps which disintegrate upon pressure is acceptable.

Pharmacotherapeutic group. Antiepileptic drugs. ATC code N03A X12.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action

Gabapentin is known to readily cross the blood-brain barrier and prevent seizures in a number of animal models of epilepsy.

Gabapentin does not alter gamma-aminobutyric acid (GABA) metabolism, has no affinity for GABA_A or GABA_B receptors, does not bind to other neurotransmitter receptors in the brain, and does not interact with sodium channels. Gabapentin binds with high affinity to the α2-δ (alpha2-delta) subunit of voltage-dependent calcium channels, which is thought to be responsible for its anticonvulsant effect in animals. Broad screening studies have not identified any other targets for gabapentin besides the α2-δ subunit.

Preclinical studies have shown that the pharmacological activity of gabapentin may be mediated through its binding to the α2-δ subunit, resulting in reduced release of excitatory neurotransmitters in various regions of the central nervous system (CNS). This mechanism may underlie the anticonvulsant effect of gabapentin; however, its role in producing this effect in humans has not been established.

Gabapentin has also demonstrated efficacy in several preclinical animal models of pain. It is hypothesized that the specific binding of gabapentin to the α2-δ subunit produces several distinct effects that may contribute to its analgesic activity in animal pain models. Gabapentin may exert analgesic effects both at the spinal cord level and in higher brain centers by interacting with descending inhibitory pain pathways. The relevance of these mechanisms to the clinical efficacy of gabapentin in humans has not been established.

Clinical Efficacy and Safety

Clinical trials of adjunctive therapy for partial seizures in children aged 3 to 12 years have shown numerically higher, but statistically non-significant, differences in the 50% responder rate in favor of gabapentin compared to placebo. A post-hoc analysis of responder rates by age group showed no significant age effect when using either continuous or binary variables (age groups 3–5 years and 6–12 years). The results of this analysis are presented in Table 1.

Table 1

Response rate to treatment (≥ 50% improvement) by treatment group and age categories. MITT* population

Age group	Placebo	Gabapentin	P value
< 6 years	4/21 (19.0 %)	4/17 (23.5 %)	0.7362
6-12 years	17/99 (17.2 %)	20/96 (20.8 %)	0.5144

* MITT (modified intent-to-treat population, including all patients who received at least one dose of either treatment) includes all randomized patients in the study who adequately completed their seizure diaries for 28 days during the baseline and double-blind phases.

Pharmacokinetics.

Absorption

Gabapentin is rapidly absorbed from the gastrointestinal tract after oral administration, independent of food intake. Time to maximum concentration is 2–3 hours. There is a tendency toward decreased bioavailability (fraction of drug absorbed) of gabapentin with increasing dose. Absolute bioavailability of gabapentin from 300 mg capsules is approximately 60%. Food, including high-fat meals, has no clinically significant effect on the pharmacokinetics of gabapentin. Pharmacokinetics are not altered with repeated dosing. Although plasma concentrations of the drug varied between 2 and 20 mcg/mL in clinical trials, this range did not determine the efficacy or safety of the drug.

Pharmacokinetic parameters are presented in Table 2.

Table 2

Summary of mean (%CV) steady-state pharmacokinetic parameters after
administration of the drug every 8 hours

Pharmacokinetic parameter	300 mg (N=7)		400 mg (N=14)		800 mg (N=14)
	Mean	%CV	Mean	%CV	Mean	%CV
Cmax (μg/mL)	4.02	(24)	5.74	(38)	8.71	(29)
tmax (h)	2.7	(18)	2.1	(54)	1.6	(76)
T1/2 (h)	5.2	(12)	10.8	(89)	10.6	(41)
AUC (0-8) μg•h/mL	24.8	(24)	34.5	(34)	51.4	(27)
Ae% (%)	ND	ND	47.2	(25)	34.4	(37)

Cmax = maximum plasma concentration at steady state;

tmax = time to reach Cmax;

T1/2 = elimination half-life;

AUC (0-8) = steady-state area under the plasma concentration-time curve from time 0 to 8 hours after drug administration;

Ae% = percentage of the administered dose excreted unchanged in urine from time 0 to 8 hours after drug administration;

ND = not available.

Distribution

Gabapentin does not bind to plasma proteins, and its volume of distribution is 57.7 liters. It crosses the blood-brain barrier: in patients with epilepsy, the concentration of gabapentin in cerebrospinal fluid is approximately 20% of the corresponding steady-state plasma concentration. Gabapentin passes into breast milk.

Metabolism

Gabapentin is minimally metabolized in humans and does not induce or inhibit liver enzymes. The drug does not interfere with the metabolism of antiepileptic drugs commonly used in clinical practice.

Excretion

Gabapentin is excreted unchanged by the kidneys. T1/2 is independent of dose and averages 5–7 hours in patients with normal renal function. Gabapentin is removed from blood during hemodialysis. Plasma clearance of gabapentin is reduced in elderly patients and in patients with impaired renal function. Elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.

Dosage adjustment is recommended for patients with impaired renal function and for patients undergoing hemodialysis.

Pharmacokinetics of gabapentin in children has been evaluated in 50 healthy volunteers aged 1 month to 12 years. Overall, when dosing is normalized per kilogram of body weight (mg/kg), plasma concentrations of gabapentin in children aged 5 years and older were similar to those in adults.

In a pharmacokinetic study of 24 healthy children aged 1 to 48 months, the area under the concentration-time curve (AUC) was approximately 30% lower, Cmax was lower, and clearance normalized per unit of body weight was higher compared to data obtained in children aged 5 years and older.

Linearity/Non-linearity

The bioavailability of gabapentin (fraction of the dose absorbed) decreases with increasing dose, indicating non-linear pharmacokinetics of the drug, specifically with respect to bioavailability parameters (F): Ae%, CL/F, Vd/F. Elimination pharmacokinetics (parameters not including F, such as CLr and T1/2) follows linear kinetics. Steady-state plasma concentrations of gabapentin are predictable based on data from single-dose administration.

Clinical characteristics.

Indications.

Epilepsy.

As monotherapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 12 years and older.

As adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 6 years and older.

Treatment of peripheral neuropathic pain in postherpetic neuralgia or diabetic neuropathy in adults.

Contraindications.

Hypersensitivity to any component of the drug.

Interaction with other medicinal products and other forms of interaction.

Cases of respiratory depression and/or sedation associated with concomitant use of gabapentin and opioids have been reported. In some reports, particular concern has been expressed regarding the use of gabapentin-opioid combinations, especially in elderly patients.

When controlled-release morphine capsules (60 mg) were administered 2 hours before gabapentin capsules (600 mg), the mean AUC of gabapentin increased by 44% compared to gabapentin administered without morphine. For this reason, careful monitoring of patients for signs of central nervous system (CNS) depression, such as somnolence, is required; the doses of morphine or gabapentin should be appropriately reduced.

No interactions between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine have been observed. Concomitant use with other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital) is possible; also with drugs that block tubular secretion and reduce renal excretion of gabapentin.

The pharmacokinetics of gabapentin are similar in healthy individuals and in patients with epilepsy who are taking these antiepileptic drugs.

Since gabapentin is minimally bound to plasma proteins, is not metabolized, and does not induce hepatic oxidative enzymes, the likelihood of its interaction with other medicinal products is very low. Concomitant administration of gabapentin with oral contraceptives containing norethisterone and/or ethinylestradiol does not affect the steady-state concentrations of these agents. When administered concomitantly with antacids containing aluminium and magnesium, the bioavailability of gabapentin is reduced by approximately 20%; therefore, it is recommended to take gabapentin no earlier than 2 hours after antacid administration. Myelotoxic drugs enhance hematotoxicity (leukopenia). Probenecid does not affect renal excretion of gabapentin. When used concomitantly with cimetidine, renal excretion of gabapentin is slightly reduced, but this reduction is not clinically significant.

Special precautions for use.

Severe skin adverse reactions (SSARs)

Severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or lead to fatal outcomes, have been reported in association with gabapentin therapy. Patients should be informed of the signs and symptoms of these reactions, and skin reactions should be closely monitored during treatment. If signs or symptoms suggestive of these reactions occur, gabapentin should be discontinued immediately, and alternative therapy (if necessary) should be considered.

If a serious reaction such as SJS, TEN, or DRESS syndrome develops during treatment with gabapentin, re-administration of gabapentin must never be attempted.

Anaphylaxis

Gabapentin may cause anaphylaxis. Reported cases have included symptoms such as difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue gabapentin immediately and seek emergency medical help if signs of anaphylaxis occur (see section "Adverse reactions").

Suicidal thoughts and behavior

Suicidal thoughts and behavior have been observed in patients treated with antiepileptic drugs for various indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior; the mechanism is unknown, but available data do not exclude the possibility of gabapentin being a contributing factor. Patients receiving antiepileptic drugs should be closely monitored for the emergence of suicidal thoughts or behavior, and appropriate treatment should be initiated if necessary. The mechanism of this risk is unknown, and available data do not rule out an increased risk with gabapentin use. Patients (and caregivers) should be advised to seek medical help immediately if signs of suicidal ideation or behavior occur.

Acute pancreatitis

Gabapentin should be discontinued if acute pancreatitis occurs during treatment.

Seizures

Although there is no evidence of rebound seizures, abrupt discontinuation of antiepileptic drugs may precipitate status epilepticus.

As with other antiepileptic drugs, in some patients receiving gabapentin, seizure frequency may increase or new types of seizures may appear. Attempts to withdraw concomitant antiepileptic therapy in treatment-resistant patients receiving multiple antiepileptic drugs in order to switch to gabapentin monotherapy are rarely successful.

Gabapentin is ineffective in treating primary generalized seizures, such as absence seizures, and may even worsen their course in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizure types, including absence seizures.

Dizziness, somnolence, loss of consciousness, and cognitive impairment

Gabapentin therapy has been associated with dizziness and somnolence, which may lead to accidental injuries (e.g., due to falls). Post-marketing data have reported cases of confusion, loss of consciousness, and cognitive disturbances. Patients should therefore be advised to exercise caution until they are familiar with the potential effects of the drug.

Concomitant use with opioids

Increased gabapentin concentrations may occur in patients requiring additional opioid therapy. Therefore, patients should be monitored for signs of central nervous system (CNS) depression, such as somnolence, sedation, and respiratory depression. The dose of gabapentin or opioids should be appropriately reduced (see section "Interaction with other medicinal products and other forms of interaction").

Respiratory depression

Gabapentin has been associated with severe respiratory depression. The risk of severe respiratory depression is increased in patients with respiratory impairment, respiratory or neurological disorders, renal insufficiency, concomitant use of CNS depressants, and in elderly patients. These patients may require dose adjustment.

Elderly patients (aged 65 years and older)

Systematic studies on the use of gabapentin in patients aged 65 years and older have not been conducted. In one double-blind study in patients with neuropathic pain, somnolence, peripheral edema, and asthenia occurred somewhat more frequently in patients aged 65 years and older compared to younger patients. Apart from these findings, no differences in the adverse effect profile were observed in clinical studies between this age group and younger patients.

Children

The long-term effects (beyond 36 weeks) of gabapentin treatment on learning ability, intelligence, and development in children and adolescents have not been adequately studied. Therefore, the benefits of prolonged therapy should be carefully weighed against the potential risks of such treatment.

Misuse, abuse, and dependence

Gabapentin may cause drug dependence, which can occur even at therapeutic doses. Cases of abuse have been reported. Patients with a history of substance abuse may be at increased risk of misuse, abuse, and dependence on gabapentin and should therefore be treated with caution. The risk of misuse, abuse, or dependence should be carefully assessed before prescribing gabapentin.

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

Dose reduction, discontinuation, or substitution with an alternative drug should be performed gradually over at least 1 week. Abrupt discontinuation of antiepileptic drugs in patients with epilepsy may provoke increased seizure frequency (status epilepticus). Caution is advised when treating patients with a history of psychiatric disorders. Alcohol and drug use may enhance CNS-related adverse effects such as confusion and ataxia.

Withdrawal symptoms

Withdrawal symptoms have been observed after discontinuation of both short- and long-term gabapentin therapy. Withdrawal symptoms may occur shortly after stopping treatment, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, sweating, tremor, headache, depression, abnormal feelings, dizziness, and malaise. The possible occurrence of withdrawal symptoms after gabapentin discontinuation may indicate drug dependence (see section "Adverse reactions"). Patients should be informed of this at the beginning of treatment. If gabapentin 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").

Laboratory tests

False-positive results may occur when semi-quantitative determination of total protein in urine is performed using rapid tests. Therefore, if necessary, additional analyses using other methods (e.g., biuret method, turbidimetric method, dye-binding tests) should be performed, or these methods should be used from the outset.

Use during pregnancy or breastfeeding.

Pregnancy period.

Risks associated with epilepsy and all antiepileptic drugs

The risk of congenital malformations in children born to mothers receiving antiepileptic drugs is increased 2-3 times. The most commonly reported malformations include cleft lip, cardiovascular defects, and neural tube defects. The risk of congenital malformations is higher with polytherapy compared to monotherapy; therefore, monotherapy should be used whenever possible. Women planning pregnancy and women of childbearing potential should be informed that antiepileptic therapy should be reviewed in case of planned pregnancy. Antiepileptic therapy should not be abruptly discontinued, as this may provoke seizures, which could seriously harm both the mother and the fetus. Developmental delay in children of mothers with epilepsy is rarely observed. It is not possible to determine whether such developmental delay is due to genetic, social factors, maternal disease, or antiepileptic therapy.

Risks associated with gabapentin therapy

Gabapentin crosses the placenta. There are insufficient data on the use of gabapentin during pregnancy. Animal studies have indicated reproductive toxicity. The potential risk to humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. It is not possible to determine whether gabapentin use during pregnancy is associated with an increased risk of congenital malformations, as both epilepsy itself and the use of antiepileptic drugs may contribute to such malformations.

Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentin in utero.

Concomitant use of gabapentin and opioids during pregnancy may increase the risk of neonatal withdrawal syndrome in newborns. Such newborns should be closely monitored.

Lactation period

Gabapentin passes into breast milk. As its effects on breastfed infants are unknown, caution should be exercised when prescribing gabapentin to lactating women. Therefore, breastfeeding should be discontinued during gabapentin therapy.

Fertility

No effects on fertility were observed in animal studies.

Ability to affect reaction speed when driving or operating machinery.

Gabapentin may have a slight or moderate effect on the ability to drive or operate machinery. Gabapentin acts on the CNS and may cause somnolence, dizziness, and other similar symptoms. Even at a mild or moderate level, these adverse effects may potentially be hazardous for patients who drive or perform other potentially dangerous work requiring special attention and rapid psychomotor responses. This is particularly relevant during the initial period of treatment and after dose increases.

Dosage and method of administration.

For oral use.

Gabapentin may be taken independently of food intake. Capsules should be swallowed whole with an adequate amount of water (e.g., one glass of water).

For all indications, the recommended dose titration regimen at the beginning of treatment for adults and children aged 12 years and older is presented in Table 3.

Table 3

Initial titration schedule
Day 1	Day 2	Day 3
300 mg once daily	300 mg twice daily	300 mg three times daily

Dosage instructions for children under 12 years of age are provided in the section below.

Discontinuation of gabapentin therapy

If gabapentin treatment needs to be discontinued, it should be done gradually over at least 1 week, regardless of the indication.

Epilepsy

Patients with epilepsy require long-term therapy. Dosage is determined according to individual tolerability and efficacy of the drug.

Adults and children aged 12 years and older

The effective dose of Gabantin is 900–3600 mg per day (divided into 3 doses).

Treatment may be initiated with dose titration as described in Table 3, or by starting with 300 mg three times daily on Day 1.

Subsequently, depending on the individual patient's response to treatment and drug tolerability, the dose may be gradually increased by 300 mg per day every 2–3 days up to a maximum dose of 3600 mg per day. Some patients may require a slower titration of gabapentin dose. The minimum time to reach a dose of 1800 mg per day is one week, 2400 mg per day is two weeks, and 3600 mg per day is generally three weeks. Data indicate that a dose of up to 4800 mg per day was well tolerated in long-term studies. The daily dose should be divided into 3 administrations. The maximum interval between doses should not exceed 12 hours to prevent seizure occurrence.

Children aged 6 years and older

Initiate treatment at a dose of 10–15 mg/kg/day. The effective dose for children aged 6 years and older is 25–35 mg/kg/day, achieved by titration over approximately 3 days.

Data indicate that a dose of 50 mg/kg body weight per day was well tolerated in long-term studies. The daily dose should be divided into 3 administrations, and the maximum interval between doses should not exceed 12 hours.

There is no need to monitor plasma drug concentrations. Gabapentin may subsequently be used in combination with other antiepileptic drugs without regard to changes in plasma gabapentin concentrations or serum concentrations of other antiepileptic drugs.

Peripheral neuropathic pain in adults

Treatment may be initiated either with dose titration as described in Table 3, or with an initial dose of 900 mg per day, divided into three doses. Subsequently, depending on the individual patient's response to treatment and drug tolerability, the dose may be gradually increased by 300 mg per day every 2–3 days up to a maximum dose of 3600 mg per day. Some patients may require a slower titration of gabapentin dose. The minimum time to reach a dose of 1800 mg per day is one week, 2400 mg per day requires two weeks, and 3600 mg per day generally requires three weeks.

For the treatment of peripheral neuropathic pain, particularly painful diabetic neuropathy and postherpetic neuralgia, efficacy and safety have not been studied for treatment periods exceeding 5 months.

If gabapentin use is required for the treatment of peripheral neuropathic pain for longer than 5 months, the physician should evaluate the patient's clinical condition and determine the need for continued treatment.

Instructions applicable to dosing for all indications

For patients with compromised general health, low body weight, or following organ transplantation, gabapentin dosage should be titrated more slowly by using a lower-dose formulation or by increasing the interval between dose escalations.

Elderly patients (aged 65 years and older)

Dosage adjustment may be required in elderly patients due to age-related decline in renal function (see Table 4).

Somnolence, peripheral edema, and asthenia may occur more frequently in elderly patients.

Patients with renal impairment

Dose adjustment is recommended for patients with impaired renal function or those undergoing hemodialysis, as described in Table 4.

Table 4

Gabapentin dosing in adults according to renal function

Creatinine clearance (mL/min)	Total daily dosea (mg/day)
≥ 80	900–3600
50–79	600–1800
30–49	300–900
15–29	150b–600
<15c	150b–300

a The total daily dose should be divided into 3 doses. Dosage reduction is recommended for patients with impaired renal function (creatinine clearance < 79 mL/min).

b Administer 300 mg every other day.

c In patients with creatinine clearance < 15 mL/min, the daily dose should be reduced proportionally to the creatinine clearance (e.g., at a creatinine clearance of 7.5 mL/min, half the daily dose should be administered compared to patients with a creatinine clearance of 15 mL/min).

Patients on hemodialysis

For anuric patients undergoing hemodialysis who have never previously received gabapentin, a loading dose of 300 to 400 mg is recommended, followed by 200–300 mg of gabapentin after each 4-hour hemodialysis session. Gabapentin should not be administered on days when dialysis is not performed.

For patients with impaired renal function undergoing hemodialysis, the maintenance dose of gabapentin should be administered according to the recommendations outlined in Table 4. In addition to the maintenance dose, it is recommended to administer an additional 200–300 mg of the drug after each 4-hour hemodialysis session.

Children

Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with or without secondary generalization in children aged 6 years and older.

Gabapentin is indicated as monotherapy in the treatment of partial seizures with or without secondary generalization in children aged 12 years and older.

Overdose

Life-threatening acute toxicity has not been observed following gabapentin overdoses up to 49 g. Although certain symptoms of overdose occurred (dizziness, ataxia, mild diarrhea, diplopia, speech difficulties, dysarthria, somnolence, lethargy, apathy), no life-threatening conditions were reported, and patients recovered following symptomatic treatment.

Reduced absorption of gabapentin at high doses may limit drug absorption in overdose, thereby minimizing its toxicity.

Overdose of gabapentin in combination with CNS depressants may result in coma.

Treatment: symptomatic therapy.

Hemodialysis may be considered depending on the clinical presentation, although accumulated experience suggests it is generally not necessary.

Hemodialysis may be indicated in patients with severe renal impairment.

In animal studies, no lethal dose was established following oral administration of gabapentin at doses up to 8 g/kg. Signs of acute toxicity observed included ataxia, labored breathing, ptosis, decreased activity, or hyperexcitability.

Adverse Reactions

Adverse reactions are classified according to frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated based on available data). Adverse reactions observed in various studies with differing frequencies are listed under the category with the highest observed frequency. Additional adverse events identified from post-marketing experience are included in the list under the category "frequency not known" (cannot be estimated based on available data) and are indicated in italics. Within each frequency group, adverse effects are listed in order of decreasing severity.

Infections and infestations: very common – viral infections; common – pneumonia, respiratory tract infections, urinary tract infections, otitis media.

Blood and lymphatic system disorders: common – leukopenia; frequency not known – thrombocytopenia.

Immune system disorders: uncommon – allergic reactions (e.g., urticaria); frequency not known – hypersensitivity syndrome (systemic reaction with various manifestations, including fever, rash, hepatitis, lymphadenopathy, eosinophilia, and sometimes other signs and symptoms), anaphylaxis (see section "Special precautions").

Metabolism and nutrition disorders: common – anorexia, increased appetite; uncommon – hyperglycemia (most frequently in patients with diabetes mellitus); rare – hypoglycemia (most frequently in patients with diabetes mellitus); frequency not known – hyponatremia.

Psychiatric disorders: common – hostility, confusion, emotional lability, depression, anxiety, increased nervousness, thought disorders; uncommon – agitation; frequency not known – hallucinations, drug dependence.

Nervous system disorders: very common – somnolence, dizziness, ataxia; common – seizures, hyperkinesia, dysarthria, amnesia, tremor, insomnia, headache, paresthesia, hypesthesia, coordination disturbances, nystagmus, increased, decreased or absent reflexes; uncommon – hypokinesia, cognitive disturbances; rare – loss of consciousness; frequency not known – other movement disorders (e.g., choreoathetosis, dyskinesia, dystonia).

Eye disorders: common – diplopia, amblyopia.

Ear and labyrinth disorders: common – vertigo; frequency not known – tinnitus.

Cardiac disorders: uncommon – palpitations.

Vascular disorders: common – arterial hypertension, vasodilation.

Respiratory, thoracic and mediastinal disorders: common – rhinitis, pharyngitis, dyspnea, bronchitis, cough; rare – respiratory depression.

Gastrointestinal disorders: common – nausea, vomiting, abdominal pain, gingivitis, constipation or diarrhea, dry mouth or throat, dyspeptic symptoms, dental changes, flatulence; uncommon – dysphagia; frequency not known – pancreatitis.

Hepatobiliary disorders: frequency not known – hepatitis, jaundice.

Skin and subcutaneous tissue disorders: common – facial edema, purpura (most commonly described as bruises occurring after physical trauma), skin rash, pruritus, acne; frequency not known – Stevens-Johnson syndrome, toxic epidermal necrolysis, eosinophilia with systemic symptoms (see section "Special precautions"), erythema multiforme, angioneurotic edema, alopecia.

Musculoskeletal and connective tissue disorders: common – myalgia, arthralgia, back pain, muscle twitching; frequency not known – myoclonus, rhabdomyolysis.

Renal and urinary disorders: frequency not known – acute renal failure, urinary incontinence.

Reproductive system and breast disorders: common – impotence; frequency not known – breast enlargement, gynecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia).

General disorders and administration site conditions: very common – increased fatigue, fever; common – peripheral edema, gait disturbance, asthenia, pain, malaise, influenza-like syndrome; uncommon – generalized edema; frequency not known – withdrawal symptoms, chest pain. Sudden death has been reported, although a causal relationship with gabapentin treatment has not been established.

Investigations: common – decreased white blood cell count, weight gain; uncommon – increased liver function tests (AST, ALT, and bilirubin); frequency not known – increased blood creatine phosphokinase levels.

Injury, poisoning and procedural complications: common – accidental injury, fractures, lacerations; uncommon – falls.

*Symptoms of withdrawal have been observed after discontinuation of both short- and long-term gabapentin treatment. Withdrawal symptoms may occur shortly after stopping treatment, usually within 48 hours. Most commonly reported symptoms include anxiety, insomnia, nausea, pain, sweating, tremor, headache, depression, abnormal feelings, dizziness, and malaise (see section "Special precautions"). The occurrence of withdrawal symptoms after gabapentin discontinuation may indicate drug dependence (see section "Adverse Reactions"). Patients should be informed about this at the beginning of treatment. If gabapentin needs to be discontinued, it is recommended to do so gradually over at least one week, regardless of the indication (see section "Dosage and administration").

Cases of acute pancreatitis have been reported during gabapentin treatment. A causal relationship with gabapentin has not been established.

Cases of myopathy with elevated creatinine levels have been reported in patients undergoing hemodialysis with end-stage renal disease.

There is evidence that respiratory infections, middle ear infections, bronchitis, and seizures were observed only in children. Aggressive behavior and hyperkinesia have also been frequently reported in children.

Shelf life. 3 years.

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

Packaging. 10 capsules in a blister; 3 or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "Pharma Start".

Manufacturer's address and place of business.
8 V. Havel Boulevard, Kyiv, 03124, Ukraine.

If adverse effects occur or if you have any questions regarding the safety of this medicinal product, please contact the Pharmacovigilance Department of ASINO UKRAINE at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine,
Tel/fax: +38 044 281 2333.