Tebantin

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

Composition:

Active ingredient: gabapentin;

1 capsule contains 300 mg of gabapentin;

Excipients: magnesium stearate; talc; pregelatinized starch; lactose monohydrate; iron oxide yellow (E 172); iron oxide red (E 172); titanium dioxide (E 171); gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: capsule contents: white or almost white crystalline powder; capsule size № 1, Coni-Snap®; upper part: pink-brown color (L570), lower part: yellow color (42087 STD YELLOW OP.C087).

Pharmacotherapeutic group.

Antiepileptic drugs. Other antiepileptic drugs. ATC code N03A X12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Gabapentin readily crosses into the brain and prevented seizures in several animal models of epilepsy. Gabapentin does not alter the metabolism of GABA (gamma-aminobutyric acid) and has no affinity for GABA_A or GABA_B receptors. It 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 hypothesized to be responsible for its anticonvulsant effect in animals. Broad-spectrum screening studies have not identified any other targets for gabapentin besides the α2-δ subunit.

Data from several preclinical studies suggest that the pharmacological activity of gabapentin may be mediated through binding to the α2-δ subunit, resulting in reduced release of excitatory neurotransmitters in various regions of the central nervous system (CNS). This activity may underlie the anticonvulsant effect of gabapentin; however, the role of this mechanism in achieving the anticonvulsant 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 leads to several different effects that may contribute to its analgesic action in animal pain models. Gabapentin may produce analgesic effects both at the spinal cord level and in higher brain centers by interacting with descending inhibitory pathways of pain sensitivity. The role of these properties in the clinical efficacy of gabapentin in humans has not been studied.

Clinical efficacy and safety.

Clinical studies of adjunctive therapy for partial seizures in children aged 3 to 12 years showed 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 did not reveal a significant age effect, 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 categories and groups. MITT population*.
Age category	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 who adequately completed daily seizure diaries for at least 28 days during the baseline and double-blind phases.

Pharmacokinetics.

Absorption.

After oral administration, maximum plasma concentrations of gabapentin are achieved within 2–3 hours. There is a tendency toward decreased bioavailability (fraction of drug absorbed) with increasing gabapentin dose. Absolute bioavailability of gabapentin following administration of 300 mg capsules is approximately 60%. Food intake, including high-fat meals, does not have a clinically significant effect on the pharmacokinetics of gabapentin.

Repeated administration does not affect the pharmacokinetics of gabapentin. Although plasma concentrations of the drug varied between 2 mcg/mL and 20 mcg/mL in clinical studies, 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 dosing 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 steady-state plasma concentration

tmax = time to reach Cmax

T1/2 = elimination half-life

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

Ae% = percentage of the 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. The volume of distribution of the drug is 57.7 L. The concentration of gabapentin in cerebrospinal fluid (CSF) of patients with epilepsy is approximately 20% of the steady-state minimum plasma concentration. Gabapentin penetrates into breast milk.

Biotransformation.

No data on gabapentin metabolism in humans have been obtained. The drug does not induce liver oxidative enzymes involved in the metabolism of medicinal products.

Elimination.

Gabapentin is excreted exclusively by the kidneys in unchanged form. The elimination half-life of gabapentin is independent of dose and averages 5–7 hours.

In elderly patients and in patients with impaired renal function, the plasma clearance of gabapentin is reduced. The elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.

Gabapentin is removed from plasma during hemodialysis. Dose adjustment is recommended for patients with renal impairment or those undergoing hemodialysis (see section "Dosage and administration").

The pharmacokinetics of gabapentin in children was evaluated in 50 healthy subjects aged 1 month to 12 years. Overall, when doses were normalized per kg of body weight (mg/kg), plasma concentrations of gabapentin in children aged 5 years and older did not differ from those in adults.

In a pharmacokinetic study of 24 healthy children aged 1 to 48 months, AUC was approximately 30% lower, Cmax was lower, and clearance 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 drug absorbed) decreases with increasing dose, indicating non-linear pharmacokinetics of the drug, specifically bioavailability parameters (F): Ae%, CL/F, Vd/F. The elimination pharmacokinetics (pharmacokinetic parameters not including F, such as CLr and T1/2) follows a linear pattern. The steady-state plasma concentration of gabapentin is predictable based on data from single-dose administration.

Clinical characteristics.

Indications.

Epilepsy.

Gabapentin is used as an adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 6 years and older (see section "Pharmacodynamics").

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

Treatment of peripheral neuropathic pain.

Gabapentin is indicated for the treatment of peripheral neuropathic pain, such as painful diabetic neuropathy and postherpetic neuralgia in adults.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients (see section "Composition").

Interaction with other medicinal products and other forms of interaction.

Cases of respiratory depression, sedation, and fatal outcomes associated with concomitant use of gabapentin and central nervous system (CNS) depressants, including opioids, have been reported in spontaneous reports and in the literature. In some reports, particular concern has been expressed regarding the use of gabapentin in combination with opioids, especially in debilitated patients, elderly patients, patients with significant respiratory disorders, patients on polypharmacy, and patients with substance use disorders.

In a study involving healthy volunteers (N = 12) who received controlled-release capsules containing 60 mg of morphine two hours prior to taking gabapentin (600 mg capsule), the mean AUC of gabapentin increased by 44% compared to cases when morphine was not administered. Therefore, when concomitant treatment with opioids and gabapentin is necessary, careful monitoring of patients is required to promptly identify symptoms of CNS depression such as somnolence, sedation, and respiratory depression, and appropriate dose reductions of gabapentin or opioids should be considered.

No interactions between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine have been observed.

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

Concomitant administration of gabapentin and oral contraceptives containing norethisterone and/or ethinylestradiol does not affect the steady-state concentrations of these agents.

Concomitant administration of gabapentin and antacids containing aluminum and magnesium reduces the bioavailability of gabapentin by up to 24%. Gabapentin should be taken no sooner than 2 hours after antacid administration.

Administration of probenecid does not interfere with renal elimination of gabapentin.

A slight decrease in renal clearance of gabapentin has been observed when co-administered with cimetidine; however, this effect is not expected to be clinically significant.

Special precautions for use.

Severe cutaneous adverse reactions (SCAR)

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

If a patient develops such serious reactions as SJS, TEN, or DRESS syndrome during treatment with gabapentin, the patient must never be rechallenged with gabapentin.

Anaphylaxis.

Gabapentin may cause anaphylaxis. In reported cases, symptoms included difficulty breathing, swelling of lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue gabapentin immediately and seek emergency medical help if symptoms 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 of which is unknown. In the post-marketing period, cases of suicidal thoughts and behavior have been reported in patients taking gabapentin (see section "Adverse reactions").

Patients (and caregivers) should be advised to contact their physician if signs of suicidal thoughts or behavior emerge. Patients should be monitored for signs of suicidal thoughts and behavior, and appropriate therapy should be considered. Discontinuation of gabapentin therapy should be considered if suicidal thoughts or behavior occur.

Acute pancreatitis.

Gabapentin should be discontinued if acute pancreatitis occurs during treatment (see section "Adverse reactions").

Seizures.

Although there is no evidence of rebound seizures with gabapentin, abrupt discontinuation of antiepileptic drugs in patients with epilepsy may lead to status epilepticus (see section "Dosage and administration").

As with other antiepileptic drugs, an increase in seizure frequency or emergence of new types of seizures may occur in some patients during treatment with gabapentin.

As with other antiepileptic drugs, attempts to discontinue concomitant antiepileptic agents to switch to gabapentin monotherapy in refractory patients receiving multiple antiepileptic drugs have rarely been successful.

Gabapentin is not considered effective in treating primary generalized seizures such as absence seizures and may exacerbate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizure types that include absence seizures.

Dizziness, somnolence, loss of consciousness, confusion, and cognitive impairment.

Treatment with gabapentin has been associated with dizziness and somnolence, which may lead to accidental injuries (due to falls). Post-marketing data have reported cases of confusion, loss of consciousness, and cognitive impairment. Therefore, patients should be advised to exercise caution until they become familiar with the potential effects of the drug.

Concomitant use with opioids and other CNS depressants.

Patients requiring concomitant treatment with central nervous system (CNS) depressants, including opioids, should be closely monitored for signs of CNS depression such as somnolence, sedation, and respiratory depression. Increased gabapentin concentrations may occur in patients receiving gabapentin and morphine concomitantly. The dose of gabapentin or CNS depressants, including opioids, should be reduced accordingly (see section "Interaction with other medicinal products and other forms of interaction").

Gabapentin should be prescribed with caution when used concomitantly with opioids due to the risk of CNS depression. In a population-based observational case-control study among patients receiving opioids, concomitant use of opioids and gabapentin was associated with an increased risk of opioid-related mortality compared to opioid monotherapy (adjusted odds ratio [aOR], 1.49 [95% CI, 1.18–1.88, p<0.001]).

Respiratory depression.

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

Elderly patients (aged 65 years and older).

Systematic studies of gabapentin use in patients aged 65 years and older have not been conducted. In one double-blind study involving patients with neuropathic pain, somnolence, peripheral edema, and weakness occurred more frequently in patients aged 65 years and older compared to younger patients. Except for these findings, clinical studies in this age group have not provided evidence of differences in the adverse event profile compared to younger patients.

Improper use, potential for abuse and dependence.

Gabapentin may cause drug dependence, including at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance abuse are at higher risk of improper use, abuse, and dependence on gabapentin and should be treated with caution. The risk of improper use, abuse, or dependence should be carefully assessed before prescribing gabapentin.

Patients taking gabapentin should be monitored for symptoms of improper use, abuse, or dependence, such as drug-seeking behavior, dose escalation, and development of tolerance.

Withdrawal syndrome.

Withdrawal symptoms have been observed after discontinuation of both short-term and long-term gabapentin treatment. Withdrawal symptoms may appear shortly after discontinuation, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, sweating, tremor, headache, depression, abnormal sensations, dizziness, and malaise. The 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 discontinuation is necessary, it is recommended to taper the dose gradually over at least one week, regardless of the indication (see section "Dosage and administration").

Laboratory tests.

Semi-quantitative urine protein tests using test strips may yield false-positive results. Therefore, if necessary, additional analyses using alternative methods (e.g., biuret method, turbidimetric method, dye-binding tests) should be performed, or these methods should be used initially.

Excipients.

Tebantin® capsules contain lactose. The product should not be administered to patients with rare hereditary conditions such as lactose intolerance, full lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy.

General risks of epilepsy and antiepileptic therapy.

The risk of congenital abnormalities in offspring of mothers treated with antiepileptic drugs is increased by 2–3 times. The most commonly reported abnormalities include cleft lip, cardiovascular malformations, and neural tube defects. Combination antiepileptic therapy, compared to monotherapy, may be associated with a higher risk of developmental malformations; therefore, monotherapy is recommended whenever possible. All pregnant women and women of childbearing potential requiring antiepileptic therapy should be referred to a specialist before initiating treatment. The need for antiepileptic therapy should be re-evaluated before planning pregnancy. Abrupt discontinuation of antiepileptic drugs is not acceptable, as it may lead to seizures and significantly worsen the condition of both mother and child. Developmental delay in offspring of mothers with epilepsy is rare. It is not possible to differentiate whether developmental delay is due to genetic disorders, social factors, maternal epilepsy, or antiepileptic drug exposure.

Risk associated with gabapentin therapy.

Gabapentin crosses the human placenta.

Data on the use of gabapentin in pregnant women are lacking or limited. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the fetus.

There is no definitive conclusion on whether gabapentin, used by women during pregnancy for epilepsy, may increase the risk of congenital abnormalities in offspring, either due to epilepsy itself or due to concomitant use of other antiepileptic drugs.

Neonatal withdrawal syndrome has been reported in newborns whose mothers took gabapentin during pregnancy. Concomitant use of gabapentin and opioids during pregnancy may increase the risk of neonatal withdrawal syndrome. Newborns should be closely monitored.

Breastfeeding.

Gabapentin passes into breast milk. Since the effect of the drug on breastfed infants has not been studied, gabapentin should be used with caution in breastfeeding women. Gabapentin may be used in breastfeeding women only if the benefit to the mother outweighs the potential risk to the infant.

Fertility.

No effects on fertility were observed in animal studies.

Ability to influence reaction speed when driving or operating machinery.

Gabapentin may have a slight or moderate influence on the ability to drive or operate machinery. Gabapentin affects the CNS and may cause somnolence, dizziness, or other similar symptoms. These adverse effects, even if mild or moderate, may be potentially hazardous for patients when driving vehicles or operating other machines, especially at the beginning of therapy and after dose escalation.

Dosage and administration.

Dosage.

For all indications, the dose titration regimen described in Table 3 is used initially. This regimen is recommended for adults and children aged 12 years and older. Dosing instructions for children under 12 years of age are provided in a separate section.

Table 3.

Dosage calculation for initial dose titration.
Day 1	Day 2	Day 3
300 mg once daily	300 mg twice daily	300 mg three times daily

Discontinuation of gabapentin

According to current clinical guidelines, gabapentin should be discontinued gradually over a minimum of 1 week, regardless of the indication.

Epilepsy.

Long-term therapy is usually required in epilepsy. The dose is determined by the physician according to individual tolerability and efficacy.

Adults and adolescents.

Effective doses in epilepsy range from 900 to 3600 mg/day. Treatment is initiated with dose titration as described in Table 3, or with a dose of 300 mg three times daily on Day 1. Subsequently, depending on individual tolerability and efficacy, the dose may be increased by 300 mg/day every 2–3 days up to the maximum dose of 3600 mg/day. Some patients may require a slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

In long-term open-label clinical studies, a dose of 4800 mg/day was well tolerated by patients. The daily dose should be divided into three doses. The maximum interval between doses should not exceed 12 hours to avoid interruptions in anticonvulsant therapy and to prevent the occurrence of seizures.

Children aged 6 years and older.

The initial dose should be 10–15 mg/kg/day. The effective dose should be achieved by titrating the drug over approximately 3 days. The effective dose of gabapentin in children aged 6 years and older is 25–35 mg/kg/day. A dose of 50 mg/kg/day has been shown to be well tolerated in long-term clinical studies. The total daily dose should be divided into equal parts (administered three times daily); the maximum interval between doses should not exceed 12 hours.

There is no need to monitor serum gabapentin levels. Additionally, gabapentin can be used in combination with other antiepileptic drugs, as it does not alter the plasma concentration of gabapentin or serum concentrations of other antiepileptic drugs.

Peripheral neuropathic pain.

Adults.

Treatment is initiated with dose titration as described in Table 3; otherwise, the starting dose of 900 mg/day should be divided into three doses. Subsequently, depending on individual tolerability and efficacy, the dose may be increased by 300 mg/day every 2–3 days up to the maximum dose of 3600 mg/day. Some patients may require a slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

The efficacy and safety of gabapentin in the treatment of peripheral neuropathic pain (e.g., painful diabetic neuropathy or postherpetic neuralgia) have not been studied in long-term clinical trials lasting more than 5 months. If a patient requires longer-term treatment (more than 5 months) with gabapentin for neuropathic pain, the physician should evaluate the patient's clinical status and determine the need for continued therapy before proceeding.

Instructions for all indications.

Patients with poor general condition or specific risk factors, such as low body weight or post-transplant status, may require slower titration, either by reducing the incremental dose or by extending the intervals between dose increases.

Geriatric patients (aged 65 years and older).

Geriatric patients may sometimes require individual dose adjustment due to possible reduced renal function (see Table 4). In elderly patients, somnolence, peripheral edema, and weakness are observed more frequently.

Renal impairment.

Patients with severe renal impairment and/or patients on hemodialysis require individual dose adjustment (see Table 4).

Table 4.

Gabapentin dosing in adult patients according to renal function.

Creatinine clearance (mL/min)	Total daily dose of gabapentin* mg/day
>80	900–3600
50–79	600–1800
30–49	300–900
15–29	150**–600
<15***	150**–300

* The total daily dose should be divided into 3 doses. Reduced doses should be used in patients with renal impairment (creatinine clearance <79 mL/min).

** Administer at a dose of 300 mg every other day.

*** For patients with creatinine clearance <15 mL/min, the daily dose should be reduced according to creatinine clearance (e.g., patients with creatinine clearance of 7.5 mL/min should receive half of the daily dose recommended for patients with creatinine clearance of 15 mL/min).

Use in patients undergoing hemodialysis.

For anuric patients undergoing hemodialysis who have never previously received gabapentin, the recommended initial loading dose is 300–400 mg*, followed by 200–300 mg* of gabapentin after every 4 hours of hemodialysis. Gabapentin should not be administered on days without hemodialysis.

The maintenance dose of gabapentin for patients on hemodialysis should be determined according to the recommendations provided in Table 4. In addition to the maintenance dose, patients undergoing hemodialysis should receive an additional 200–300 mg* of gabapentin after every 4 hours of hemodialysis.

*Administer gabapentin formulations at the appropriate dosage.

Route of administration.

For oral use.

Gabapentin may be taken with or without food. The medication should be taken with sufficient fluid (e.g., a glass of water).

Children.

Gabapentin is indicated for the treatment of epilepsy in children: as adjunctive therapy in children aged 6 years and older, and as monotherapy in children aged 12 years and older.

The long-term effects (more than 36 weeks) of gabapentin on learning ability, intelligence, and development in children and adolescents have not been adequately studied. Therefore, potential risks should be considered when deciding on the need for prolonged therapy.

Overdose.

No acute life-threatening toxic reactions have been reported following gabapentin doses up to 49 g/day.

Symptoms of overdose included dizziness, double vision, slurred speech, somnolence, loss of consciousness, lethargy, and mild diarrhea. All patients fully recovered with supportive treatment. Reduced absorption of gabapentin at high doses may limit drug absorption and reduce overdose-related toxic effects.

Overdose of gabapentin, particularly when combined with other CNS depressants, may result in coma.

Although gabapentin can be removed by hemodialysis, based on previous experience, this is usually not necessary. However, hemodialysis may be indicated in patients with severe renal impairment.

In studies in mice and rats, the lethal dose of gabapentin could not be determined, even with doses as high as 8000 mg/kg. Symptoms of acute toxicity in animals included ataxia, labored breathing, ptosis, decreased activity, or, conversely, increased excitability.

Adverse reactions.

During epilepsy (adjunctive therapy or monotherapy) and neuropathic pain studies, the following adverse reactions were observed (listed according to their frequency and system organ class): very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10000 to <1/1000), and very rare (<1/10000). If the frequency of adverse effects differed across various studies, data on the highest frequency were included in the report.

Additional adverse events identified from post-marketing experience are included in the list under the category "frequency unknown" (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.

System organ class	Adverse reactions
Infections and infestations
Very common	Viral infection
Common	Pneumonia, respiratory infection, urinary tract infection, infection, otitis media
Blood and lymphatic system disorders
Common	Leukopenia
Frequency unknown	Thrombocytopenia
Immune system disorders
Uncommon	Allergic reactions (e.g., urticaria)
Frequency unknown	Hypersensitivity syndrome (systemic reaction with various manifestations, namely fever, rash, hepatitis, lymphadenopathy, eosinophilia and, sometimes, other signs and symptoms), anaphylaxis (see section "Special warnings and precautions for use")
Metabolism and nutrition disorders
Common	Anorexia, increased appetite
Uncommon	Hyperglycemia (most commonly in patients with diabetes mellitus)
Rare	Hypoglycemia (most commonly in patients with diabetes mellitus)
Frequency unknown	Hyponatremia
Psychiatric disorders
Common	Hostility, confusion and emotional lability, depression, anxiety, nervousness, abnormal thinking
Uncommon	Psychomotor hyperactivity
Frequency unknown	Suicidal ideation, hallucinations, drug dependence
Nervous system disorders
Very common	Somnolence, dizziness, ataxia
Common	Seizures, hyperkinesia, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances (paraesthesia, hypaesthesia), coordination disturbances, nystagmus, increased, decreased or absent reflexes
Uncommon	Hypokinesia, cognitive disturbance
Rare	Loss of consciousness
Frequency unknown	Other movement disorders (including choreoathetosis, dyskinesia, dystonia)
Eye disorders
Common	Visual disturbances, e.g., amblyopia or diplopia
Ear and labyrinth disorders
Common	Vertigo
Frequency unknown	Tinnitus
Cardiac disorders
Uncommon	Palpitations
Vascular disorders
Common	Hypertension, vasodilatation
Respiratory, thoracic and mediastinal disorders
Common	Dyspnea, bronchitis, pharyngitis, cough, rhinitis
Rare	Respiratory depression
Gastrointestinal disorders
Common	Vomiting, nausea, dental abnormalities, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, abdominal distension
Uncommon	Dysphagia
Frequency unknown	Pancreatitis
Hepatobiliary disorders
Frequency unknown	Hepatitis, jaundice
Skin and subcutaneous tissue disorders
Common	Facial edema, purpura (most commonly described as bruises after trauma), rash, pruritus, acne
Frequency unknown	Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (see section "Special warnings and precautions for use"), erythema multiforme, angioneurotic edema, alopecia
Musculoskeletal and connective tissue disorders
Common	Arthralgia, myalgia, back pain, muscle contractions
Frequency unknown	Rhabdomyolysis, myoclonic seizures
Renal and urinary disorders
Frequency unknown	Acute renal failure, urinary incontinence
Reproductive system and breast disorders
Common	Erectile dysfunction
Frequency unknown	Galactorrhea, gynecomastia, sexual dysfunction (including libido changes, ejaculation disorders, anorgasmia)
General disorders and administration site conditions
Very common	Increased fatigue, fever
Common	Peripheral edema, gait disturbance, weakness, pain, discomfort, influenza-like syndrome
Uncommon	Generalized edema
Frequency unknown	Withdrawal reactions*
Investigations
Common	Decreased white blood cell count, weight increased
Uncommon	Elevated liver function tests (AST, ALT) and bilirubin
Frequency unknown	Elevated blood creatine phosphokinase
Injury, poisoning and procedural complications
Common	Accidental injury, fractures, lacerations
Uncommon	Falls

*After discontinuation of short-term and long-term treatment with gabapentin, withdrawal symptoms were observed. Withdrawal symptoms may occur shortly after discontinuation, usually within 48 hours. The most commonly reported symptoms included anxiety, insomnia, nausea, pain, sweating, tremor, headache, depression, abnormal sense of well-being, dizziness, and malaise (see section "Special precautions for use"). The occurrence of withdrawal symptoms after discontinuation of gabapentin may indicate drug dependence (see section "Adverse reactions"). Patients should be informed about this at the beginning of treatment. If discontinuation of gabapentin is necessary, it is recommended to do so gradually over a period of at least 1 week, regardless of the indication (see section "Dosage and administration").

Cases of acute pancreatitis have been reported during treatment with gabapentin. The relationship to gabapentin has not been established (see section "Special precautions for use").

In patients with end-stage renal disease undergoing hemodialysis, cases of myopathy with elevated creatine kinase levels have been reported.

Cases of respiratory tract infections, otitis media, seizures, and bronchitis have been reported only in clinical studies involving children. In addition, aggressive behavior and hyperkinesia were frequently reported in pediatric studies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

Keep out of reach and sight of children.

Store at a temperature not exceeding 25 °C.

Packaging.

10 capsules in a blister, 5 or 10 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Gedeon Richter Plc., Hungary.

Manufacturer's address and place of business.

H-1103 Budapest, Demrédi út 19-21, Hungary