Neurontin

Neurontin®

Suicidal ideation and behavior

There are reports of the occurrence of suicidal thoughts or behavior in patients treated with antiepileptic drugs for various indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a small increase in the risk of suicidal ideation and behavior. The mechanism for this increased risk is unknown and available data do not exclude the possibility of such an increased risk for gabapentin.

Therefore, patients receiving these drugs should be closely monitored for signs of suicidal ideation or behavior. In such patients, the need for appropriate treatment should be considered. Patients or their caregivers should seek medical attention if signs of suicidal thoughts or behavior occur.

Acute pancreatitis

If acute pancreatitis develops while taking gabapentin, the possibility of discontinuing the drug should be assessed.

Convulsions ("oo" syndrome).

As with other antiepileptic drugs, gabapentin may cause an increase in the frequency of seizures or the appearance of a different type of seizure.

As with other antiepileptic drugs, attempts to discontinue all concomitant antiepileptic drugs in order to initiate gabapentin monotherapy in cases of treatment refractory in patients taking multiple antiepileptic drugs are generally unsuccessful.

Gabapentin is not thought to be effective for primary generalized seizures, such as absence seizures, and may even worsen such seizures in some patients. In this regard, gabapentin should be used with caution in patients with mixed seizures, including absence seizures.

Opioid analgesics

Patients who require concomitant therapy with opioid analgesics should be closely monitored for signs of central nervous system depression such as somnolence, sedation, and respiratory depression. Patients receiving gabapentin and morphine concomitantly may experience increased gabapentin concentrations. The dose of gabapentin and opioid analgesics should be reduced accordingly (see section "Interactions with other drugs").

Elderly patients

Systematic studies have not been conducted in patients aged 65 years and older taking gabapentin. In a double-blind study of gabapentin for neuropathic pain, patients aged 65 years and older had a higher incidence of somnolence, peripheral edema, and asthenia compared with patients aged <65 years. With the exception of these results, clinical examination of this group of patients showed that their profile of adverse reactions did not differ from the rest.

Children

The effect of long-term therapy (more than 36 weeks) with gabapentin on learning ability, intelligence and development of children and adolescents has not been well studied. The ratio of possible risks and benefits should be assessed when prescribing long-term therapy.

Abuse and addiction

The post-marketing surveillance database contains reports of cases of drug abuse and dependence. As with any drug that affects the central nervous system, clinicians should carefully review patients' drug abuse history and monitor patients for possible signs of gabapentin abuse (eg, drug diversion, development of resistance to gabapentin therapy, inappropriate dosage increases). drug).

DRESS syndrome

(drug reaction with eosinophilia and systemic symptoms)

Severe life-threatening hypersensitivity reactions, such as drug rash with associated eosinophilia and systemic symptoms, have been reported while taking antiepileptic drugs, including gabapentin. It must be remembered that early signs of a hypersensitivity reaction, such as fever, lymphadenopathy, can develop even in the absence of a skin rash. If such symptoms occur, immediate examination of the patient is necessary. If no other reason is found other than the use of gabapentin, the use of the drug should be discontinued.

Anaphylaxis

Taking gabapentin can lead to the development of anaphylaxis. The following symptoms and signs were noted in cases of anaphylaxis while taking gabapentin - difficulty breathing, swelling of the lips, throat and tongue, and a marked decrease in blood pressure was also noted, requiring urgent medical intervention. Patients should be warned that if signs or symptoms of anaphylaxis develop, they should stop taking the drug and seek medical attention.

Laboratory tests

False-positive results have been reported when gabapentin and other anticonvulsants were used concomitantly with Ames N-Multistix SG® urinary protein test strips. To determine protein in urine, it is recommended to use the more specific precipitation method of sulfosalicylic acid.

Effect on the central nervous system

During treatment with gabapentin, cases of dizziness and drowsiness have been observed, which may increase the likelihood of accidental injury (from a fall). Cases of confusion, loss of consciousness and mental impairment have also been reported during the post-marketing period. Therefore, patients should be advised to use caution until they are aware of the possible effects of this drug.

When used simultaneously with opioid analgesics, an increase in the concentration of gabapentin in the blood plasma may be observed. Therefore, the patient should be closely monitored for signs of central nervous system (CNS) depression, such as somnolence, sedation, and respiratory depression. Doses of gabapentin or opioid analgesics should be reduced accordingly (see section "Interactions with other drugs").

Combined use with antacids

It is recommended to take gabapentin approximately 2 hours after taking the antacid.

Neurontin film-coated tablets 600 mg 50 pcs. in Moscow

Pharmacological action: Prevents the occurrence of epileptic seizures when inducing seizures with maximum electric shock and pentylenetetrazole in mice and rats, as well as in other preclinical models (for example, lines with genetically determined epilepsy, etc.). The relevance of these models to human epilepsy has not been established.

Gabapentin is structurally similar to the neurotransmitter GABA, but does not alter the radioligand binding of GABA to the GABAA or GABAB receptors, is not metabolized to GABA or a GABA receptor agonist, and does not inhibit the uptake or breakdown of GABA. In studies using the radioligand binding method, gabapentin at concentrations up to 100 μM did not show affinity for a number of other receptors, including benzodiazepine, glutamate, N-methyl-D-aspartate, quisqualate, kainate, glycine (strychnine-insensitive and strychnine-sensitive), alpha1 -, alpha2- and beta-adrenergic, adenosine A1 and A2, muscarinic and nicotinic cholinergic, dopamine D1 and D2, H1-histamine, serotonin 5-HT1 and 5-HT2, opiate mu-, delta and kappa, cannabinoid 1, as well as to the binding sites of voltage-sensitive calcium channels (labeled with nitrendipine or diltiazem) or voltage-sensitive sodium channels (labeled with 20-alpha-benzoate-batrachotoxin A). In addition, gabapentin did not affect the cellular uptake of dopamine, norepinephrine and serotonin.

in vitro studies

Using radiolabeled gabapentin, gabapentin binding sites were discovered in rat brain tissue, including the neocortex and hippocampus. A protein in animal brain tissue with high affinity for gabapentin has been identified as an accessory subunit of the voltage-activated calcium channel. The clinical significance of this binding has not yet been established.

In experimental studies, gabapentin prevents allodynia and hyperalgesia, and especially the pain response in various models of neuropathic pain in rats and mice (models of streptozocin-induced diabetes, spinal cord injury, etc.). In addition, it reduces the pain response in models of peripheral inflammation, but does not affect direct pain-related behavior. The relevance of these models to human pain has not been established.

Efficacy of gabapentin as an adjuvant antiepileptic therapy

in adults and children (3 years and older) with refractory partial seizures was established in multicenter, placebo-controlled, double-blind, parallel-group clinical studies.

Evidence of effectiveness was obtained from three studies involving 705 patients (aged 12 years and older) and one study involving 247 children (aged 3 to 12 years). All patients included in these studies had a history of at least 4 partial epileptic seizures per month, despite the use of one or more antiepileptic drugs at therapeutic doses, and on their prescribed antiepileptic treatment regimen, seizures were observed during the 12-week baseline period (for children - within 6 weeks). For patients with ongoing epileptic seizures (at least 2, and in some studies - 4 seizures per month), gabapentin or placebo was added to ongoing therapy for 12 weeks. Efficacy was assessed by the number of patients whose seizure frequency decreased by 50% or more compared to baseline, and the “response rate” was calculated using the formula (T-B)/(T+B), where B is the baseline frequency of epileptic seizures and T is the frequency of epileptic seizures in the patient during treatment. Response rates ranged from 1 to +1. A value of zero indicates no change; complete disappearance of seizures gives a value of 1, an increase in the frequency of seizures gives positive values for the response coefficient. A 50% reduction in the frequency of epileptic seizures corresponds to a response coefficient of 0.33.

In the first study, gabapentin at a dose of 1200 mg/day, divided into 3 doses, was compared with placebo. The response rate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebo group; differences between groups were statistically significant. The response rate was also higher in the gabapentin group (−0.199) than in the placebo group (−0.044); the differences also reached a degree of statistical significance.

The second study compared gabapentin (1200 mg/day in 3 doses, n=101) with placebo (n=98), but to determine the dose-response effect, the study additionally included two smaller groups of patients who were prescribed gabapentin at a dose of 600 mg/day (n=53) and 1800 mg/day (n=54). The response rate in the gabapentin 1200 mg/day group (16%) was higher than in the placebo group (8%), but the difference was not statistically significant. The response rate in the gabapentin 600 mg/day group (17%) was also not significantly higher than in the placebo group, but the response rate in the 1800 mg/day group (26%) was statistically higher than in the placebo group. who took a placebo. The response rate in patients receiving gabapentin 1200 mg/day (−0.103) was higher than in the placebo group (−0.022), but this difference was also not statistically significant (p = 0.224). A better response was observed in the group taking gabapentin at a dose of 600 mg/day (−0.105) and at a dose of 1800 mg/day (−0.222) than in patients taking 1200 mg/day, while in the group taking gabapentin at a dose of 1800 mg/day, a statistically significant difference was achieved compared to placebo.

The third study compared gabapentin (900 mg/day in 3 doses, n=111) with placebo (n=109) and additionally included a group of patients (n=52) who were prescribed 1200 mg/day to study the dose-response effect. gabapentin. There were statistically significant differences in response rates in the gabapentin 900 mg/day group (22%) compared with placebo (10%). Response rates in the gabapentin 900 mg/day (−0.119) and 1200 mg/day (−0.184) groups were statistically significantly higher than those in the placebo group (−0.027).

In all three of the above studies, the effect of gabapentin in preventing secondary generalized tonic-clonic seizures showed statistically significant results and positive trends in almost all patients included in these studies.

Analysis of the response rate in the pooled data from all three studies at all doses used (gabapentin - n = 162, placebo - n = 89) also indicates a significant advantage of gabapentin over placebo in reducing the frequency of secondary generalized tonic-clonic seizures.

Two of the three controlled studies used more than one dose of gabapentin. Each of these studies did not find a significant increase in response in a dose-dependent manner. However, a general trend toward increased effectiveness of gabapentin with increasing dose is evident.

A fourth study in pediatric patients (3 to 12 years) compared gabapentin 25–35 mg/kg/day (n=118) with placebo (n=127). The response rate for all patients with partial seizures was significantly higher with gabapentin (−0.146) than with placebo (−0.079).

Studies in children aged 1 month to 3 years receiving 40 mg/kg/day gabapentin (N = 38) compared with placebo (N = 38) showed no statistically significant differences in response rates or response rates in study patients .

Efficacy of gabapentin for the control of postherpetic neuralgia

was evaluated in two randomized, double-blind, placebo-controlled, multicenter studies involving 563 patients. The criterion for patient selection was persistence of pain for more than 3 months after healing of skin rashes caused by herpes zoster. Gabapentin was prescribed at a dose of 1800 to 3600 mg/day in 3 divided doses. Both studies found significant differences from placebo across the dose range used. Typically, significant pain relief was observed during the first week of treatment and persisted until the end of treatment.

In studies in mice and rats receiving oral gabapentin at doses greater than 8000 mg/kg, the lethal dose has not been established. The following symptoms of acute toxicity were observed in animals: ataxia, dyspnea, ptosis, sedation, decreased activity or agitation.

In experiments on mice and rats that were given gabapentin in their food for 2 years, a statistically significant increase in the incidence of acinar cell adenoma and pancreatic carcinoma in male rats was found when receiving a high dose of 2000 mg/kg/day. At this dose, the peak plasma concentration of gabapentin in rats was 10 times higher than that in humans receiving gabapentin at a dose of 3600 mg/day. Pancreatic acinar cell carcinoma had no effect on survival, did not metastasize, and did not show local invasion. The relevance of these data to carcinogenic risk in humans has not been established.

In standard in vitro

and
in vivo
, gabapentin did not show mutagenic or genotoxic properties.

There were no effects on fertility or reproduction in rats treated with gabapentin at doses up to 2000 mg/kg (approximately 5 times the maximum recommended human dose on a mg/m2 basis).

Pharmacokinetics

. Gabapentin does not undergo significant metabolism in humans.

The bioavailability of gabapentin decreases with increasing dose and is 60, 47, 34, 33 and 27% after taking doses of 900, 1200, 2400, 3600 and 4800 mg/day (divided into 3 doses), respectively. Food intake has a minor effect on the rate and extent of absorption of gabapentin (14% increase in the area under the curve AUC and Cmax).

Plasma protein binding is less than 3%, the apparent volume of distribution after intravenous administration at a dose of 150 mg is 58 ± 6 l. In patients with epilepsy, Cmin in the cerebrospinal fluid was approximately 20% of the corresponding plasma level.

Gabapentin is eliminated by renal excretion. T1/2 is 5–7 hours and does not depend on the dose and subsequent multiple doses. The elimination rate constant, plasma clearance and renal clearance of gabapentin are directly proportional to creatinine clearance. In the elderly and in patients with impaired renal function, the plasma clearance of gabapentin is reduced. Gabapentin can be removed from plasma by hemodialysis.

Patients with weakened renal function, the elderly and those on hemodialysis require dose adjustment. Gabapentin has not been studied in children with renal impairment. Patients with age-related weakening of renal function may require a dose reduction.

Because gabapentin is not metabolized by the liver, studies have not been conducted in people with impaired liver function.

A study of the pharmacokinetics of gabapentin in children with epilepsy showed that children aged 3 to 4 years, in order to achieve the same average plasma concentration that is observed in children from 5 to 12 years with a daily dose of 30 mg/kg, require a daily dose of 40 mg /kg.

Specific comparative studies of the pharmacokinetics of gabapentin in men and women have not been conducted, however, there appear to be no significant differences in the pharmacokinetic parameters of gabapentin in men and women.

Pharmacokinetic differences in people of different racial groups have not been studied, however, since gabapentin is eliminated primarily by the kidneys and creatinine clearance does not differ significantly between people of different races, the existence of such differences is not expected.

special instructions

Suicidal ideation and behavior
Antiepileptic drugs, including gabapentin, may increase the risk of suicidal ideation or behavior. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs demonstrated a small increase in the risk of suicidal ideation and behavior. The mechanism for increasing the risk of developing suicidal ideation is unknown, but for gabapentin it cannot be excluded. Therefore, patients receiving these drugs should be closely monitored for new or worsening depression, the emergence of suicidal thoughts or behavior, and any changes in behavior. Patients or their caregivers should seek medical attention if signs of suicidal thoughts or behavior occur.

Acute pancreatitis

If acute pancreatitis develops while taking gabapentin, the possibility of discontinuing the drug should be assessed.

Convulsions ("oo" syndrome).

As with other antiepileptic drugs, gabapentin may cause an increase in the frequency of seizures or the appearance of a different type of seizure.

As with other anticonvulsants, attempts to discontinue all concomitant antiepileptic drugs in order to initiate gabapentin monotherapy in cases of treatment refractory in patients taking multiple anticonvulsants are generally unsuccessful.

Elderly patients

Systematic studies have not been conducted in patients aged 65 years and older taking gabapentin. In a double-blind study of gabapentin for neuropathic pain, patients aged 65 years and older had a higher incidence of somnolence, peripheral edema, and asthenia compared with patients aged <65 years. Apart from these results, clinical examination of this group of patients showed that their side effect profile did not differ from the rest.

Children

The effect of long-term therapy (more than 36 weeks) with gabapentin on the learning ability, intelligence and development of the child has not been sufficiently studied. The ratio of possible risks and benefits should be assessed when prescribing long-term therapy. Abuse and addiction. The post-marketing surveillance database contains reports of cases of drug abuse and dependence. As with any drug that affects the central nervous system, clinicians should carefully review patients' drug abuse history and monitor patients for possible signs of gabapentin abuse (eg, drug seeking, development of resistance to gabapentin therapy, inappropriate dosage increases). ).

DRESS syndrome

Severe life-threatening hypersensitivity reactions, such as drug rash with associated eosinophilia and systemic symptoms, have been reported while taking antiepileptic drugs, including gabapentin. It is necessary to remember this. that early signs of a hypersensitivity reaction, such as fever, lymphadenopathy, can develop even in the absence of skin rash. If such symptoms occur, immediate examination of the patient is necessary. If no other reason is found other than the use of gabapentin, the use of the drug should be discontinued.

Anaphylaxis

Taking gabapentin can lead to the development of anaphylaxis. The following symptoms and signs were noted in cases of anaphylaxis while taking gabapentin: difficulty breathing, swelling of the lips, throat and tongue, and a marked decrease in blood pressure was also noted, requiring urgent medical intervention. Patients should be warned that if signs or symptoms of anaphylaxis develop, they should stop taking the drug and seek medical attention.

Laboratory tests

When gabapentin and other anticonvulsants were co-administered, false-positive results have been reported when measuring urinary protein using Ames N-Multistix SG test strips. To determine protein in urine, it is recommended to use the more specific precipitation method of sulfosalicylic acid.

Effect on the central nervous system

When used simultaneously with opioid analgesics, an increase in the concentration of gabapentin in the blood plasma may be observed. In this regard, the patient needs to be closely monitored for the development of signs of CNS depression, such as drowsiness, sedation, and respiratory depression. Doses of gabapentin or opioid analgesics should be reduced accordingly (see section "Interactions with other drugs").

Combined use with antacids

It is recommended to take gabapentin approximately 2 hours after taking the antacid.