*The modified intention-to-treat population was defined as all patients randomized to study medication in patients whose seizure diaries were available during both the baseline and double-blind phases during both the baseline and double-blind phases.

Pharmacokinetics

Absorption

After oral administration, the maximum plasma concentration (Cmax) is recorded after 2-3 hours. is obtained. The absolute bioavailability of a 300 mg capsule is approximately 60%. Food, including food rich in fat, does not have a clinically significant effect on the pharmacokinetics of gabapentin.

Pharmacokinetics of gabapentin does not depend on repeated administration. Although plasma concentrations of gabapentin in clinical studies are typically 2 mg/ml to 20 mcg/ml, such concentrations are not predictive of safety and efficacy.

Distribution

Gabapentin practically does not bind to plasma proteins (less than 3%). The distribution volume is 57.7 liters. In patients suffering from epilepsy, the concentration of gabapentin in the cerebrospinal fluid is approximately 20% of the corresponding steady-state plasma concentration. Gabapentin penetrates into breast milk.

Metabolism

There are no data on the metabolism of gabapentin in humans. The drug does not induce mixed-function oxidative liver enzymes involved in the metabolism of medicinal substances.

Exclusion

The elimination half-life of gabapentin is independent of dose and averages 5-7 hours. Gabapentin is excreted unchanged from the body only through the kidneys. The clearance of gabapentin from the blood plasma decreases in the elderly and in patients with impaired renal function. Excretion rate clearance, plasma clearance and renal clearance are directly proportional to creatinine clearance. Gabapentin is removed from plasma during hemodialysis. Dosage adjustment is recommended in patients with renal failure and/or hemodialysis patients.

Pharmacokinetics of gabapentin in children was determined in 50 subjects aged 1 month to 12 years. In general, the concentrations of gabapentin in the blood plasma of children over 5 years old when dosing in mg/kg are the same as in adults. In a pharmacokinetic study in 24 healthy children aged 1-48 months, approximately 30% lower exposure (AUC), lower Cmax and higher clearance per body weight were observed in children over 5 years of age.

Linearity/non-linearity

Gabapentin bioavailability (fraction of the absorbed dose) decreases with increasing dose, which gives a linear character to the pharmacokinetic parameters, including the bioavailability parameter (F), for example, Ae%, CL/F, Vd/F. Elimination pharmacokinetics (pharmacokinetic parameters that do not include the bioavailability parameter (F) such as CLr and T1/2) are best described as linear pharmacokinetics. Steady-state plasma concentrations of gabapentin can be estimated from single-dose data.

 

Instructions for use

During epilepsy

• It is indicated as adjunctive therapy in adults and children over 6 years of age with or without secondary generalized partial seizures.

• It is indicated as monotherapy in the treatment of generalized partial seizures with or without secondary generalized seizures in adults and children over 12 years of age.

In case of pain associated with peripheral neuropathy

• It is indicated in the treatment of peripheral diabetic neuropathies such as painful diabetic neuropathy in adults and post-herpetic neuralgia.

 

Contraindications

Hypersensitivity to any of the components contained in the preparation.

 

Special instructions and precautions

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

Severe, life-threatening systemic hypersensitivity reactions, such as eosinophilia and drug reaction with systemic symptoms, have been reported in patients receiving antiepileptic drugs, including gabapentin. It should be noted that early manifestations of hypersensitivity reactions, such as fever or lymphadenopathy, may occur even in the absence of a rash. If such signs/symptoms occur, the patient's condition should be evaluated immediately; Treatment with gabapentin should be discontinued unless another source of these symptoms is confirmed.

Anaphylaxis

Gabapentin can cause anaphylaxis. Signs and symptoms requiring emergency medical attention in reported cases of anaphylaxis include difficulty breathing, edema of the lips, throat, and tongue, and hypotension. If signs and symptoms of anaphylaxis occur, gabapentin should be discontinued and medical attention should be sought immediately.

Suicidal ideation and behavior

Suicidal thoughts and behaviors have been reported in patients taking antiepileptic drugs. The mechanism of the risk is unknown, and the available data do not exclude the possibility of an increased risk for gabapentin. Patients (and their caregivers) should be advised to seek medical attention if symptoms of suicidal ideation or behavior develop.

Acute pancreatitis

Gabapentin should be discontinued if acute pancreatitis develops in patients treated with gabapentin.

Seizures

Despite the absence of symptoms of ricochet seizures during treatment with gabapentin, abrupt discontinuation of the use of anticonvulsants in patients with epilepsy may lead to an increase in the frequency of epileptic seizures. As with other antiepileptic drugs, some patients may experience an increased frequency of seizures or develop new types of seizures.
As with other antiepileptic drugs, attempts to simultaneously discontinue antiepileptic drugs in difficult-to-treat patients receiving multiple antiepileptic drugs with the goal of switching to gabapentin monotherapy have rarely been successful. In primary-generalized seizures such as absences, gabapentin is not an effective drug and may cause exacerbation of such seizures in some patients. Thus, gabapentin should be used with caution in patients suffering from mixed seizures, including absences.
Dizziness, drowsiness, loss of consciousness, confusion and mental disorders

Treatment with gabapentin has been accompanied by dizziness and drowsiness, which may increase the frequency of accidental trauma (due to falls). Also, during the post-marketing use of gabapentin, there have been reports of confusion (confusion), loss of consciousness, fogging of consciousness, and impaired mental functioning. For this reason, patients should be advised to take precautions until the potential effects of their drug are known.

Use with opioids

Patients requiring concomitant opioid therapy should be carefully monitored for signs of CNS depression such as drowsiness, sedation, and respiratory failure. At the same time, the concentration of gabapentin in the body of patients using morphine and gabapentin may increase. The dose of gabapentin or opioids should be reduced accordingly.

Inhibition of breathing

Gabapentin can cause severe respiratory failure. Patients with impaired respiratory function, respiratory disease, neurological disease, or renal failure, as well as patients taking CNS depressant drugs and the elderly may be at higher risk of this severe side effect. In these patients, drug dosage adjustment may be required.

Use in the elderly (over 65 years old).

No systematic clinical studies with gabapentin have been conducted in patients over 65 years of age.

In a double-blind study of patients with neuropathic pain, slightly higher rates of somnolence, peripheral edema, and asthenia were found in patients over 65 years of age than in younger patients. Apart from these results, clinical studies in this age group do not show a different adverse effect profile than that observed in younger patients.

Use in children

The effects of long-term treatment with gabapentin (more than 36 weeks) on education, intelligence and development in children and adolescents have not been adequately studied. Therefore, the benefits of long-term treatment must be weighed against the potential risks of such treatment.

Drug abuse and addiction

Cases of abuse and dependence have been reported in the postmarketing period. It is recommended to carefully assess the patient's history of drug abuse and carefully monitor them for possible signs of gabapentin abuse, such as drug-seeking behavior, increasing the dose, and the risk of developing tolerance.
Laboratory studies

When adding gabapentin to other anticonvulsant drugs, it was determined that the determination of protein in the urine with the Ames N-Multistix SG test strip gave false positive results. It is recommended to use precipitation with sulfosalicylic acid, which is considered a more specific method for determining protein in urine.

Capsules of the drug contain lactose. Patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use the drug.

 

Interaction with other drugs

There are spontaneous and literature reports of respiratory depression and/or sedation associated with the use of gabapentin and opioids. In some of these data, the authors believe that this is of particular concern with the combination of gabapentin and opioids, especially in elderly patients.

In a study of healthy volunteers (N=12), when a 60 mg slow-release morphine capsule was administered 2 hours before a 600 mg gabapentin capsule, the mean gabapentin AUC was increased by 44% compared to gabapentin administered without morphine. For this reason, patients requiring concomitant opioid therapy should be carefully monitored for signs of CNS depression such as drowsiness, sedation, and respiratory failure, and the dose of gabapentin or opioid should be reduced accordingly.

The interaction between gabapentin and phenobarbital, phenytoin, valproic acid and carbamazepine has not been determined. At steady state, the pharmacokinetics of gabapentin were similar in both healthy subjects and patients receiving other anticonvulsants.

When gabapentin is used simultaneously with oral contraceptives containing norethindrone and/or ethinyl estradiol, no changes in the pharmacokinetics of both components were observed. When gabapentin is used simultaneously with antacids containing aluminum and magnesium, its bioavailability is reduced by 24%. It is recommended to take gabapentin approximately 2 hours after taking antacids.

Probenecid does not affect the renal excretion of gabapentin. When used simultaneously with cimetidine, a slight decrease in the renal excretion of gabapentin can be detected, which is not of clinical significance.

 

Use during pregnancy and lactation

Pregnancy

Epilepsy and the risk associated with the use of antiepileptic drugs in general

The risk of birth defects increases 2-3 times in children whose mothers take anti-epileptic drugs. More cleft lips, defects of the cardiovascular system and defects of the neural tube were noted. The use of several antiepileptic drugs may increase the risk of congenital malformations compared to monotherapy, therefore, monotherapy should be used whenever possible.

Specialist advice is essential for women who may be pregnant and women of reproductive age; the necessity of using antiepileptic drugs in women planning pregnancy should be reconsidered. Antiepileptic treatment should not be stopped suddenly, as this may lead to persistent epileptic seizures, which can have serious consequences for mother and child. In rare cases, developmental delay has been reported in children whose mothers suffer from epilepsy. It is not possible to determine whether the developmental delay is due to genetics, social factors, congenital epilepsy or antiepileptic treatment.

Risk associated with gabapentin

Gabapentin crosses the placental barrier.

There are no or limited data on the use of gabapentin in pregnant women.

No reproductive toxicity was found in animal studies. The potential risk to humans is unknown. Tegapen should not be used during pregnancy without a doctor's prescription and supervision. Gabapentin can be used during pregnancy only in cases where the benefit to the mother is greater than the potential risk to the fetus and newborn (developmental defects, retardation of mental and physical development). The association of gabapentin use during pregnancy with an increased risk of birth defects is inconclusive, since epilepsy itself already carries such a risk, and antiepileptic drugs are used during treatment in every recorded pregnancy.

Lactation period

Gabapentin penetrates into breast milk. Because the effect of the drug on a breastfed baby is unknown, caution should be exercised when gabapentin is taken during lactation. Gabapentin should be used in lactating women only if the benefit outweighs the risk.

Fertility
In animal studies, the effect of the drug on fertility was not revealed.

 

Effects on the ability to drive vehicles and other potentially dangerous mechanisms

The drug Gabapentin has a weak or moderate effect on the ability to drive a vehicle and other potentially dangerous mechanisms.

Gabapentin can affect the central nervous system, causing drowsiness, dizziness, and similar symptoms. Even if these side effects are only mild or moderate, they can pose a potential hazard to patients who drive vehicles and operate other potentially dangerous machinery. This mainly occurs at the beginning of treatment and after increasing the dose.

 

Method of use and dosage

Inside, food intake is accepted regardless of time.

The dose should be taken as a whole, together with sufficient liquid (with 1 glass of water).

For all indications in adults and adolescents over 12 years of age, the starting dose and its adjustment are as shown in the table below.

Dosage guidelines for children under 12 years of age are given under a separate subheading below in this section.

Table 1.  Dosing scheme – initial titration