Gabata 100

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT GABATA 100 / GABATA 300 / GABATA 400

Composition:

Active substance: gabapentin;

1 capsule contains 100 mg of gabapentin;

Excipients: maize starch, anhydrous lactose, talc, hard gelatin capsule No. 4;
Capsule shell composition: gelatin, sodium lauryl sulfate, titanium dioxide (E 171).

1 capsule contains 300 mg of gabapentin;

Excipients: maize starch, anhydrous lactose, talc, hard gelatin capsule No. 1;
Capsule shell composition: gelatin, sodium lauryl sulfate, titanium dioxide (E 171), yellow iron oxide (E 172).

1 capsule contains 400 mg of gabapentin;

Excipients: maize starch, anhydrous lactose, talc, hard gelatin capsule No. 0;
Capsule shell composition: gelatin, sodium lauryl sulfate, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Capsules.

Main physicochemical properties:

100 mg capsules: hard gelatin capsules No. 4 with white cap and white body, marked with blue ink «216» on the capsule body, filled with crystalline powder from white to almost white;

300 mg capsules: hard gelatin capsules No. 1 with yellow cap and yellow body, marked with blue ink «215» on the capsule body, filled with crystalline powder from white to almost white;

400 mg capsules: hard gelatin capsules No. 0, filled with crystalline powder from white to almost white;

Pharmacotherapeutic group.

Antiepileptic drugs. Other antiepileptics. ATC code N03AX12.

Pharmacological Properties

Pharmacodynamics.

The exact mechanism of action of gabapentin is unknown. Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid), but its mechanism of action differs from that of other active substances interacting with GABA synapses, including valproate, barbiturates, benzodiazepines, GABA-transaminase inhibitors, GABA reuptake inhibitors, GABA agonists, and GABA prodrugs. In *in vitro* studies using radiolabeled gabapentin, a novel peptide binding site in the rat brain has been described, including the neocortex and hippocampus, which may be related to the anticonvulsant and analgesic effects of gabapentin and its structural analogs. The gabapentin binding site has been identified as the alpha2-delta subunit of voltage-sensitive calcium channels.

Gabapentin does not bind, at clinically relevant concentrations, to other common drug or neurotransmitter receptors in the brain, including GABA_A, GABA_B, benzodiazepine, glutamate, glycine, or N-methyl-D-aspartate (NMDA) receptors.

Gabapentin does not interact with sodium channels *in vitro*, thus differentiating it from phenytoin and carbamazepine. Gabapentin partially reduces the response to the glutamate agonist N-methyl-D-aspartate (NMDA) in some *in vitro* test systems, but only at concentrations exceeding 100 μM, which are not achieved *in vivo*. Gabapentin slightly reduces the release of monoamine neurotransmitters *in vitro*. Administration of gabapentin to rats increases GABA turnover in several brain regions, similar to sodium valproate in other brain areas. The significance of these various effects of gabapentin for its anticonvulsant activity remains to be established. In animals, gabapentin readily enters the brain and prevents seizures induced by maximal electroshock, by chemical convulsants including inhibitors of GABA synthesis, and in genetic seizure models.

Pharmacokinetics.

Following oral administration, gabapentin is rapidly absorbed from the gastrointestinal tract, independent of food intake. No interaction with food has been observed. Peak plasma concentrations are reached within 2–3 hours. Drug dose and plasma concentration are linearly related. Repeated administration does not affect its pharmacokinetic parameters. The absolute bioavailability is approximately 59% and remains unchanged during chronic treatment.

Gabapentin does not bind to plasma proteins. The drug crosses the blood-brain barrier; in patients with epilepsy, its concentration in cerebrospinal fluid is approximately 20% of the corresponding equilibrium plasma concentration.

Gabapentin is virtually not 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.

The drug is excreted exclusively by the kidneys in unchanged form. Elimination half-life is dose-independent and averages 5–7 hours in individuals with normal renal excretory function. Gabapentin can be removed from plasma by hemodialysis.

Clinical characteristics.

Indications.

Epilepsy.

Gabapentin is used as an add-on 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.

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.

Interaction with other medicinal products and other forms of interaction.

Antiepileptic drugs. Pharmacokinetic studies have shown no significant changes in plasma concentrations of phenytoin, carbamazepine, valproic acid, or phenobarbital when co-administered with gabapentin as background therapy. In these same studies, no changes in the pharmacokinetics of gabapentin were observed.

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

Antacids. Concomitant administration of gabapentin with antacids containing aluminium or magnesium reduces the bioavailability of gabapentin by up to 24%. Gabapentin should be taken no sooner than 2 hours after antacid intake.

Cimetidine. A slight reduction in renal clearance of gabapentin has been observed when administered concomitantly with cimetidine; however, this effect is not expected to be of clinical significance.

Morphine. In a study involving healthy volunteers (N = 12) who received controlled-release capsules containing 60 mg of morphine 2 hours prior to gabapentin (600 mg), a 44% increase in mean AUC of gabapentin was observed compared to when morphine was not administered. Therefore, careful monitoring of patients is required when morphine and gabapentin are used concomitantly to promptly identify symptoms of CNS depression such as somnolence, and appropriate dose reductions of gabapentin or morphine should be considered.

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

Alcohol and misuse of other CNS-active drugs. Possible enhancement of CNS-related adverse effects of gabapentin (such as somnolence, ataxia, etc.).

Myelotoxic medicinal products. Enhanced hematotoxicity (leukopenia).

Special precautions for use.

In case of acute pancreatitis developing during gabapentin therapy, discontinuation of gabapentin is recommended (see section "Side effects").

Despite the lack of evidence for reactive seizures associated with gabapentin use, abrupt withdrawal of antiepileptic drugs in patients with epilepsy may lead to the development of status epilepticus (see section "Dosage and administration").

The dose should be reduced, the drug discontinued, or replaced with another (alternative) agent gradually over a period of at least 1 week.

As with other antiepileptic agents, in some patients, gabapentin may increase the frequency of seizures or lead to the emergence of new types of seizures.

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. Available data do not exclude an increased risk with gabapentin.

Therefore, patients should be monitored for signs of suicidal thoughts and behavior, and consideration should be given to initiating appropriate treatment. Patients (and caregivers) should be advised to seek medical help immediately if symptoms of suicidal thoughts or behavior occur.

As with other antiepileptic drugs, attempts to discontinue concomitant antiepileptic agents in patients with refractory epilepsy who are receiving more than one antiepileptic drug in order to achieve monotherapy with gabapentin have a low success rate.

Gabapentin is not considered an effective treatment for primary generalized seizures such as absence seizures, and it may exacerbate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizure types, including absence seizures.

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

Cases of abuse and dependence have been reported in post-marketing surveillance. Therefore, patient history regarding substance abuse should be carefully evaluated, and patients should be monitored for possible signs of gabapentin abuse, such as attempts to obtain the drug, dose escalation, or development of tolerance.

Use in elderly patients. 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 over 65 years of age compared to younger patients. Except for these findings, clinical trials in this age group have not demonstrated differences in the adverse event profile compared to younger patients.

Gabapentin therapy has been associated with dizziness and somnolence, which may potentially increase the risk of accidental injuries in elderly patients.

Post-marketing reports have also included loss of consciousness, confusion, and development of psychiatric disorders during gabapentin treatment.

Therefore, patients should be advised to exercise caution until their individual response to gabapentin is known.

Patients who are taking opioids concomitantly with gabapentin require careful monitoring for early signs of central nervous system (CNS) depression, such as somnolence and respiratory depression.

Concomitant use of morphine and gabapentin may increase gabapentin concentrations. The dose of gabapentin or opioids should be reduced.

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Severe, life-threatening systemic hypersensitivity reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS), have been reported in patients taking antiepileptic drugs, including gabapentin.

It is important to note that early signs of hypersensitivity, such as fever or lymphadenopathy, may appear before the onset of rash. If such symptoms occur, gabapentin therapy should be discontinued immediately unless an alternative cause for the symptoms is identified.

Gabapentin may cause anaphylactic shock or angioedema, which may occur immediately after the first dose or at any time during treatment. Symptoms reported in documented cases include difficulty breathing, swelling of lips, throat, and tongue, hypotension requiring emergency intervention. Patients should discontinue gabapentin immediately and seek medical help if they experience any signs of anaphylaxis or angioedema.

Laboratory tests.

False-positive results may occur when measuring total protein in urine semi-quantitatively using rapid test strips. Therefore, such results should be confirmed using methods based on a different analytical principle, such as the biuret test, turbidimetric method, or dye-binding method, or these alternative methods should be used initially.

Caution is recommended when treating patients with a history of psychotic disorders.

This medicinal product contains anhydrous lactose and therefore should not be used in patients with lactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

General risks of epilepsy and antiepileptic therapy.

The risk of congenital malformations in children whose mothers took antiepileptic drugs during pregnancy is increased by 2–3 times. The most commonly reported malformations include cleft lip/palate, cardiovascular anomalies, and neural tube defects. Combination antiepileptic therapy may be associated with a higher risk of developmental abnormalities compared to monotherapy; therefore, monotherapy is recommended whenever possible. All pregnant women and women of childbearing potential requiring antiepileptic therapy should consult a specialist before starting 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 children 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.

Adequate data on the use of gabapentin in pregnant women are lacking. 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.

It has not been established whether gabapentin use during pregnancy increases the risk of congenital malformations in children due to maternal epilepsy itself and gabapentin use, or due to concomitant use of other antiepileptic drugs.

Gabapentin passes into breast milk. Since the effects of gabapentin on infants have not been studied, gabapentin should be used with caution during breastfeeding. The use of gabapentin during breastfeeding is justified only when the benefit to the mother outweighs the potential risk to the infant.

Fertility.

In animal studies, gabapentin did not affect fertility.

Ability to influence reaction speed when driving or operating machinery.

Gabapentin affects the central nervous system and may cause somnolence, dizziness, or other similar symptoms. These side effects, even if mild or moderate, may be potentially hazardous when driving vehicles or operating machinery, particularly at the beginning of therapy and after dose increases.

Method of administration and dosage.

For oral use.

Gabapentin can be taken independently of food intake. The medication should be taken with an adequate amount of liquid (e.g., a glass of water).

Table 3

Dosage schedule for initial dose titration in adults and children aged 12 years and older
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 children aged 12 years and older: 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 starting dose of 300 mg three times daily on Day 1. Then, 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 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 administrations. The maximum interval between doses should not exceed 12 hours to avoid interruption of anticonvulsant therapy and to prevent seizure occurrence.

Children aged 6 to 12 years.

The initial dose should be 10–15 mg/kg body weight/day. The effective dose should be achieved by titration over approximately 3 days. The effective dose of gabapentin in children aged 6 years and older is 25–35 mg/kg body weight/day. A dose of 50 mg/kg body weight/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 plasma concentrations of gabapentin or other antiepileptic drugs in serum are not altered.

Peripheral neuropathic pain.

Adults.

Treatment is initiated with dose titration as described in Table 3, or with an initial dose of 900 mg/day divided into three doses. Then, depending on individual tolerability and efficacy, the dose may be increased by 300 mg/day every 2–3 days up to a maximum of 3600 mg/day. Some patients may require 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.

Patients with poor general health or certain complicating 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.

Elderly patients (over 65 years of age).

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

Patients with renal impairment.

Patients with severe renal impairment and/or patients on hemodialysis require individual dose adjustment (see Table 4). Capsules of gabapentin 100 mg are recommended for such patients.

Table 4

Gabapentin dosing in renal impairment.

Creatinine clearance (mL/min)	Total daily dose of gabapentin* (mg/day)
>80 (normal creatinine clearance)	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 100 mg three times daily on alternate days.

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

Dosing for patients undergoing hemodialysis.

For anuric patients undergoing hemodialysis who have never previously received gabapentin, the recommended 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 specified in Table 4. In addition to the maintenance dose, patients on hemodialysis are recommended to take 200–300 mg of the drug after every 4 hours of hemodialysis.

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.

Overdose.

Even when the drug was taken at doses up to 49 g/day, no acute life-threatening toxic reactions were observed.

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

With supportive therapy, patients' condition returned completely to normal.

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, despite using doses up to 8000 mg/kg. Symptoms of acute toxicity in animals included ataxia, labored breathing, ptosis, decreased activity, or, conversely, increased excitability.

Gabapentin overdose, especially when combined with other CNS depressants, may lead to coma.

Adverse Reactions

During the use of medicinal products containing the active substance gabapentin in epilepsy (as adjunctive or monotherapy treatment) and neuropathic pain, the following adverse reactions have been reported.

Infections and parasitic diseases: viral infection, pneumonia, respiratory infection, urinary tract infection, otitis media, infection.

Blood and lymphatic system disorders: leucopenia, thrombocytopenia.

Immune system disorders: allergic reactions (e.g., urticaria), hypersensitivity syndrome (DRESS syndrome), systemic reactions with various manifestations including fever, rash, hepatitis, lymphadenopathy, eosinophilia, and other signs and symptoms.

Metabolism and nutrition disorders: increased appetite, anorexia, hyperglycemia (most commonly observed in patients with diabetes), hypoglycemia (most commonly observed in patients with diabetes), hyponatremia.

Psychiatric disorders: hostility, confusion and emotional lability, depression, anxiety, restlessness, abnormal thinking, hallucinations.

Nervous system disorders: dizziness, somnolence, ataxia, seizures, hyperkinesia, dysarthria, tremor, insomnia, headache, sensory disturbances (paresthesia, hypesthesia), coordination disturbances, nystagmus, increased, decreased or absent reflexes, amnesia, memory impairment, movement disorders (including choreoathetosis, dyskinesia, dystonia), loss of consciousness, hypokinesia, cognitive impairment.

Eye disorders: visual disturbances (e.g., amblyopia, diplopia).

Ear and labyrinth disorders: vertigo, tinnitus.

Cardiac disorders: palpitations.

Vascular disorders: arterial hypertension, vasodilation.

Respiratory, thoracic and mediastinal disorders: dyspnea, bronchitis, pharyngitis, cough, rhinitis.

Gastrointestinal disorders: vomiting, nausea, dental disorders, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or dry throat, abdominal distension, pancreatitis.

Hepatobiliary disorders: hepatitis, jaundice.

Skin and subcutaneous tissue disorders: facial edema, purpura (most commonly described as bruises following trauma), rash, pruritus, acne, Stevens-Johnson syndrome, angioneurotic edema, erythema multiforme, alopecia, drug rash with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, back pain, muscle twitching, rhabdomyolysis, myoclonic seizures.

Renal and urinary disorders: urinary incontinence, acute renal failure.

Reproductive system and breast disorders: impotence, breast enlargement, gynecomastia, sexual dysfunction (including changes in libido, ejaculation disorders, and anorgasmia).

General disorders and administration site conditions: increased fatigue, fever, peripheral or generalized edema, gait disturbance, weakness, pain, discomfort, influenza-like syndrome, withdrawal reactions (mainly anxiety, insomnia, nausea, pain, sweating), chest pain. Cases of sudden death have been reported; however, a clear causal relationship with gabapentin use has not been established, falls.

Investigations: decreased white blood cell count, weight gain, increased liver function tests (AST, ALT) and bilirubin, increased creatine phosphokinase levels, fluctuations in blood glucose levels in patients with diabetes.

Injury and poisoning: accidental injury, fractures, abrasions.

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

In patients with end-stage renal disease on hemodialysis, cases of myopathy with elevated creatine kinase (CK) 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 have been frequently observed in pediatric studies.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

Capsules 100 mg

7 capsules in a blister; 1 blister in a cardboard box.

10 capsules in a blister; 1 blister in a cardboard box.

Capsules 300 mg

10 capsules in a blister; 1 blister in a cardboard box.

14 capsules in a blister; 1 blister in a cardboard box.

Capsules 400 mg

10 capsules in a blister; 1 blister in a cardboard box.

14 capsules in a blister; 1 blister in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Alkem Laboratories Ltd.

Manufacturer's address and place of business.

167 Mahatma Gandhi, Udio Nagar, Dabhel, Daman, 396210, India.