Drug title

Neurontin (Gabapentin)

Pharmacological action

The exact mechanism of action of gabapentin is not known.

The chemical structure of gabapentin is similar to that of the neurotransmitter GABA (gamma-aminobutyric acid), but its mechanism of action differs from other active substances that interact with GABA synapses, such as valproates, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA reuptake inhibitors, GABA agonists and GABA prodrugs. In vitro studies with the radioisotope-labeled gabapentin in the rat brain revealed new areas of the drug's binding to proteins, including the neocortex and hippocampus, which may be relevant to the anticonvulsant and analgesic activity of gabapentin and its derivatives. The binding site of gabapentin has been found to be the α-2-δ (alpha-2-delta) subunit of potential-dependent calcium channels.

In clinically relevant concentrations, gabapentin does not bind to other common drug and neurotransmitter receptors present in the brain, including GABA, GABB, benzodiazepine, glutamate, glycine or N-methyl-d-aspartate.

Gabapentin does not interact with sodium channels under in vitro conditions, which distinguishes it from phenytoin and carbamazepine. In a number of in vitro test systems, the use of gabapentin led to a partial reduction in response to the glutamate agonist N-methyl-d-aspartate (NMDA), but only at concentrations greater than 100 μmol/L, which is not achievable under in vivo conditions. Under in vitro conditions gabapentin administration leads to a slight decrease in monoamine neurotransmitter release. Gabapentin administration to rats increases the rate of GABA metabolism in some brain regions, similar to the effect of sodium valproate, but the effect is seen in other parts of the brain. The relationship of the various effects of gabapentin described to its anticonvulsant activity remains to be established. In animals, gabapentin readily penetrates the brain tissue and prevents seizures provoked by maximal electroshock, chemical drugs, including inhibitors of GABA synthesis, as well as due to genetic factors.

Clinical efficacy and safety

In a clinical trial of adjuvant therapy of partial seizures in children aged 3 to 12 years, it was demonstrated that there was a quantitative, but not statistically significant difference in seizure frequency by 50% in gabapentin group compared to placebo group. Additional analysis of the frequency of response to therapy as a function of age (when considering age as a continuous variable or when separating two age subgroups: 3-5 years and 6-12 years) did not reveal a statistically significant effect of age on therapy efficacy.

Pharmacokinetics

Absorption

After oral administration Cmax of gabapentin in blood plasma is reached within 2-3 hours. Bioavailability of gabapentin tends to decrease with increasing drug dose. Absolute bioavailability when taking 300 mg capsules is approximately 60%. Food, including those with high fat content, has no clinically significant effect on the pharmacokinetic parameters of gabapentin.

Pharmacokinetics of gabapentin does not change with repeated administration of the drug. Although plasma concentrations of gabapentin typically ranged from 2-20 µg/mL in clinical trials, this did not predict either the efficacy or safety of the drug. Parameters of pharmacokinetics are presented in the table.

Contraindications to use

• Use as monotherapy of partial convulsions with and without secondary generalization in children under 12 years of age;
• Use as an adjunctive agent in the treatment of partial convulsions with and without secondary generalization in children under 3 years of age;
• for the treatment of neuropathic pain in children and adolescents under 18 years of age;
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption (for capsules);
• Hypersensitivity to gabapentin or excipients of the drug.

Caution should be exercised when the drug is prescribed in renal failure.

Use in pregnancy and lactation

Overall risk due to epilepsy and antiepileptic drugs

The risk of giving birth to children with congenital anomalies in mothers who are treated with anticonvulsants increases 2 to 3 times. The most common are cleft lip and palate, cardiovascular defects, and neural tube defects. At the same time, taking several anticonvulsants may be associated with a greater risk of malformations than in the case of monotherapy. Therefore, if possible, one of the anticonvulsant drugs should be used. Women of childbearing age, as well as all women who are likely to become pregnant, should be consulted by a qualified specialist. If a woman is planning to become pregnant, the need to continue anticonvulsant therapy should be reassessed. At the same time, anticonvulsants should not be abruptly withdrawn, as this may lead to a recurrence of seizures with severe consequences for the mother and child. In rare cases, developmental delays have been observed in children whose mothers have epilepsy. It cannot be determined whether the developmental delay is due to genetic or social factors, maternal disease, or anticonvulsant therapy.

Risk due to gabapentin

Gabapentin crosses the placental barrier. Congenital malformations and adverse pregnancy outcomes have been reported with gabapentin, but adequate controlled studies of its use in pregnant women are lacking, and no definitive conclusion can be made about the association of gabapentin with an increased risk of congenital anomalies or other adverse developmental outcomes with its use during pregnancy. The risk of congenital anomalies is 2-3 times greater in offspring of women treated with antiepileptic drugs. In animal experiments, toxicity of the drug to the fetus was shown. There are no data regarding the possible risk in humans. Therefore, gabapentin should be used during pregnancy only if the anticipated benefit to the mother justifies the possible risk to the fetus.

In the cases that have been reported, it is uncertain whether or not the use of gabapentin during pregnancy is associated with an increased risk of malformations, firstly because of the presence of epilepsy itself and secondly because of the use of other anticonvulsant drugs.

Breastfeeding

Gabapentin is excreted with breast milk and its effects on the breastfed infant are unknown, so Neurontin® should only be prescribed during breastfeeding if the benefit to the mother clearly outweighs the risk to the infant.

Fertility

No effect of gabapentin on fertility has been noted in animal studies.

Use in renal dysfunction

Caution should be exercised when the drug is prescribed in renal insufficiency.

Administration in children

Its use as monotherapy of partial convulsions with and without secondary generalization in children under 12 years of age; as additional agent in treatment of partial convulsions with and without secondary generalization in children under 3 years of age; for treatment of neuropathic pain in children and adolescents under 18 years of age is contraindicated.

Use in elderly patients.

Due to age-related reduction in renal function, elderly patients may require dosage adjustment.

Indications for Neurontin

treatment of neuropathic pain in adults 18 years of age and older;

monotherapy of partial seizures with and without secondary generalization in adults and children over 12 years of age;

as an adjunctive agent in the treatment of partial seizures with and without secondary generalization in adults and children 3 years of age and older.

Dosing regimen

The drug is taken orally with plenty of fluid (e.g. a glass of water), regardless of meals. It is allowed to divide the tablets in half.

If it is necessary to reduce the dose, cancel the drug or replace it with an alternative medicine, this should be done gradually over at least one week.

Neuropathic pain in adults

The initial dose is 900 mg/day in 3 doses in equal doses. Subsequently, depending on the patient's response to therapy and tolerability of the drug, the dose may be increased by 300 mg/day every 2-3 days, up to a maximum of 3600 mg/day. In some patients, a slower increase in dose may be appropriate. Minimum time to increase the dose to 1800 mg/day is 1 week, 2400 mg/day - 2 weeks, and to reach a maximum daily dose of 3600 mg/day it should be at least 3 weeks.

It should be taken into account that when using Neurontin® at a dose higher than 1800 mg/day, no additional efficacy is noted.

Treatment may be started immediately with a dose of 900 mg/day (300 mg 3 times/day) or the dose may be increased gradually to 900 mg/day during the first 3 days according to the following scheme:

• Day 1 - 300 mg of the drug once a day;
• Day 2 - 300 mg 2 times a day;
• Day 3 - 300 mg 3 times a day.

In treatment of peripheral neuropathic pain, such conditions as the painful form of diabetic neuropathy and postherpetic neuralgia, the effectiveness and safety of using the drug for a period longer than 5 months have not been studied in clinical trials. If a patient requires continued therapy for peripheral neuropathic pain beyond 5 months, the treating physician should evaluate the patient's clinical status and determine the need for additional therapy.

Partial seizures.

Epilepsy usually requires long-term treatment. The dose of the drug in this case is determined by the attending physician depending on the individual tolerance and effectiveness of the drug.

In adults and children over 12 years old an effective dose is 900 to 3600 mg/day. Therapy may be started with a dose of 300 mg 3 times/day on the first day or increased gradually to 900 mg according to the scheme described above (see subsection "Neuropathic pain in adults").

Subsequently, the dose may be increased to a maximum of 3600 mg/day (divided into 3 equal doses). Good tolerability of the drug in doses up to 4800 mg/day has been noted. The maximum interval between doses in triple dosing should not exceed 12 hours in order to avoid recurrence of seizures.

In children aged 3-12 years the initial dose varies from 10 to 15 mg/kg/day, which is administered in equal doses 3 times/day and increased up to effective dose within approximately 3 days. The effective dose of gabapentin in children aged 5 years and older is 25-35 mg/kg/day in equal doses of 3 doses. Effective dose of gabapentin in children aged 3 to 5 years is 40 mg/kg/day in equal doses of 3 doses. There is good tolerability of the drug in doses up to 50 mg/kg/day in long-term use. The maximum interval between doses of the drug should not exceed 12 hours in order to avoid recurrence of seizures.

There is no need to monitor the plasma concentration of gabapentin. It may be used in combination with other anticonvulsants without regard to changes in its plasma concentrations or concentrations of other anticonvulsants in the serum.

In patients in a severe condition, such as underweight, after organ transplantation, etc., the dose should be increased more slowly, either using lower doses, or at longer intervals before increasing the dose.

Due to age-related decreases in renal function, elderly patients may require dose adjustments (see Table 1 for more information). Drowsiness, peripheral edema, and asthenia may be more common in elderly patients.

In patients on hemodialysis who have not previously taken gabapentin, a saturation dose of 300-400 mg is recommended and then 200-300 mg should be administered after every 4 hours of hemodialysis. For patients with reduced renal function on dialysis, the maintenance dose of gabapentin should be adjusted according to the recommendations in Table 1. In addition to maintenance therapy, administration of 200-300 mg of gabapentin after each 4-hour dialysis session is recommended.