Neuralgin capsules 300 mg bottle #100

Instructions for use Neuralgin capsules 300 mg bottle No. 100

Composition

active ingredient: gabapentin;

1 capsule contains 300 mg of gabapentin;

excipients: anhydrous lactose, corn starch, talc;

capsule shell:

300 mg capsules – gelatin, titanium dioxide (E 171), D&C yellow dye No. 10 (quinoline yellow E 104).

Dosage form

Capsules.

Main physicochemical properties:

Hard gelatin capsules, size 1, "Konisnap", yellow body and cap with a matte surface. The cap is marked "Gabapentin/300 mg" in blue, and the body is marked with the "P" logo or without a logo, or there are no inscriptions on the cap and body. The capsules are filled with white powder.

Pharmacotherapeutic group

Antiepileptic drugs. ATX code N03A X12.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Gabapentin readily penetrates the brain and prevents seizures in a number of animal models of epilepsy. Gabapentin does not alter GABA (gamma-aminobutyric acid) metabolism 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-gated calcium channels, which is thought to be responsible for its anticonvulsant effects in animals. A broad range of screening studies has not shown that gabapentin binds to targets other than α2-δ.

Several preclinical studies suggest that the pharmacological activity of gabapentin may be mediated by binding to the α2-δ subunit through a reduction in the release of excitatory neurotransmitters in various parts of the central nervous system (CNS). This activity may underlie the anticonvulsant effect of gabapentin, but its role in achieving this effect in humans has not yet been studied.

Gabapentin has also been shown to be effective in a number of preclinical animal studies modeling pain. It is believed that the specific binding of gabapentin to the α2-δ subunit causes several different effects that could provide analgesic effects in animal pain models. Gabapentin may exert analgesic effects at both the spinal cord and higher brain centers by interacting with descending inhibitory pathways of pain sensitivity. The role of these properties in the clinical efficacy of the drug in humans has not been studied.

Clinical efficacy and safety

Clinical trials of adjunctive therapy for partial onset seizures in children aged 3 to 12 years demonstrated a numerically greater but not statistically significant difference in the 50% response rate in favor of gabapentin compared with placebo. Additional post-hoc analyses of responder rates by age showed no significant effect of age 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 (≥50% improvement) by treatment category and group. MITT population*

* The MITT (modified population of patients who took at least one dose of a drug) includes all patients randomized to the study who were able to complete seizure diaries to a sufficient degree for assessment for 28 days during the baseline and double-blind phases.

Pharmacokinetics

Absorption

After oral administration of gabapentin, the maximum plasma concentration (Cmax) is reached within 2-3 hours. There is a tendency for the bioavailability of gabapentin (the absorbed portion of the drug) to decrease with increasing dose. The absolute bioavailability of gabapentin when administered as a 300 mg capsule is approximately 60%. Food, including fatty foods, has no clinically significant effect on the pharmacokinetics of gabapentin.

Multiple administration does not affect the pharmacokinetics of gabapentin. Although plasma concentrations of the drug in clinical studies ranged from 2 to 20 μg/mL, this value did not determine the efficacy and safety of the drug.

Pharmacokinetic parameters are listed in Table 2.

Table 2

Summary of mean (%CV) steady-state pharmacokinetic parameters after administration of the drug every 8 hours

Cmax = maximum steady-state plasma concentration;

tmax = time to reach Cmax;

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

Ae% = percentage of 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 the cerebrospinal fluid (CSF) of patients with epilepsy is approximately 20% of the equilibrium minimum plasma concentration. Gabapentin penetrates into breast milk.

Biotransformation

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

Breeding

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

In elderly patients and in patients with renal impairment, 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 by hemodialysis. In patients with impaired renal function or those undergoing hemodialysis, dose adjustment is recommended (see section 4.2).

The pharmacokinetics of gabapentin in children were evaluated in 50 healthy volunteers aged 1 month to 12 years. Overall, when calculated on a dose per kilogram of body weight (mg/kg), plasma concentrations of gabapentin in children aged 5 years and older did not differ from those in adults.

A pharmacokinetic study in 24 healthy children aged 1 to 48 months showed approximately 30% lower AUC, lower Cmax and higher clearance per unit body weight compared to data obtained in children aged 5 years and older.

Linearity/nonlinearity

The bioavailability of gabapentin (the absorbed portion of the drug) decreases with increasing dose, which indicates the nonlinearity of the pharmacokinetics of the drug, namely the bioavailability parameters (F): Ae%, CL/F, Vd/F. Elimination pharmacokinetics (pharmacokinetic parameters that do not include F, such as CLr and T1/2) have a linear pattern. The equilibrium plasma concentration of gabapentin is predictable based on data from a single dose of the drug.

Indication

Epilepsy

As adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 6 years and older.

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, such as painful diabetic neuropathy and postherpetic neuralgia in adults.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the drug.

Interaction with other medicinal products and other types of interactions

Spontaneous reports and the literature have described cases of respiratory depression and/or sedation associated with the concomitant use of gabapentin and opioids. In some reports, the authors express particular concern about the use of the combination of gabapentin and opioids, especially in elderly patients.

In a study in healthy volunteers (N=12), when 60 mg of morphine controlled-release capsules were administered 2 hours before 600 mg of gabapentin capsules, the mean AUC of gabapentin increased by 44% compared to the AUC of gabapentin administered without morphine. Therefore, patients should be closely monitored for signs of CNS depression such as drowsiness; the dose of gabapentin or morphine should be reduced as appropriate.

There are no reported cases of interactions between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine.

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

Concomitant use of gabapentin and oral contraceptives containing norethisterone and/or ethinyl estradiol does not affect the steady-state concentrations of these drugs.

Antacids containing Al3+ and Mg2+ reduce the bioavailability of gabapentin by approximately 20%, so it is recommended to take the drug 2 hours after taking an antacid.

Myelotoxic drugs increase hematotoxicity (leukopenia).

Renal excretion of gabapentin is not altered by probenecid.

A slight decrease in the renal excretion of gabapentin was observed when it was taken with cimetidine, although this is not expected to be of clinical significance.

The pharmacokinetics of gabapentin are similar in healthy volunteers and in patients with epilepsy receiving antiepileptic drugs.

Application features

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome)

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

Anaphylaxis

Gabapentin may cause anaphylaxis. The following symptoms have been reported: difficulty breathing, swelling of the lips, throat and tongue, and hypotension, requiring emergency treatment. Patients should be instructed to discontinue gabapentin immediately and seek emergency medical attention if symptoms of anaphylaxis occur (see section 4.8).

Suicidal thoughts and behavior

Suicidal ideation and behavior have been reported in patients treated with antiepileptic drugs for several indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal ideation and behavior, the mechanism of which is unknown, but the available data do not allow us to exclude the possibility of an effect of gabapentin.

Therefore, signs of suicidal ideation and behavior should be monitored and appropriate treatment should be considered. Patients (and caregivers) should be advised to seek medical advice if suicidal ideation and behavior develop.

Acute pancreatitis

If acute pancreatitis occurs during the use of gabapentin, discontinuation of gabapentin is indicated (see section "Adverse reactions").

Convulsive seizures

Although there is no evidence of reversible seizures, abrupt discontinuation of anticonvulsant medication may precipitate status epilepticus.

As with other anticonvulsants, some patients may experience an increase in seizure frequency or new types of seizures while taking gabapentin.

Attempts to discontinue concomitant antiepileptic drugs in order to switch to gabapentin monotherapy in refractory patients receiving multiple antiepileptic drugs are rarely successful.

Gabapentin is not considered effective in the treatment of primary generalized seizures, such as absence seizures, and may even worsen such seizures in some patients. Therefore, gabapentin should be prescribed with caution in patients with mixed seizures, including absence seizures.

Dizziness, drowsiness, loss of consciousness and impaired mental activity

Gabapentin treatment has been associated with dizziness and drowsiness, which may lead to accidental injury (due to falls). Postmarketing data have reported cases of confusion, loss of consciousness, and mental impairment. Therefore, patients should be advised to exercise caution until they are fully aware of the potential effects of the drug.

Concomitant use with opioids

In patients requiring additional opioid therapy, increased gabapentin concentrations may occur. Therefore, patients should be monitored for signs of CNS depression such as drowsiness, sedation, and respiratory depression. The dose of gabapentin or opioids should be reduced accordingly (see section 4.5).

Respiratory depression

Gabapentin has been associated with severe respiratory depression. Patients with impaired respiratory function, diseases of the respiratory and nervous systems, renal failure, concomitant use of drugs that depress CNS function, and elderly patients are at increased risk of severe respiratory depression. These patients may require dose adjustment.

Elderly patients (aged 65 years and over)

There have been no systematic studies of gabapentin in patients over 65 years of age. In one double-blind study in patients with neuropathic pain, somnolence, peripheral edema, and asthenia were slightly more common in patients over 65 years of age than in younger patients. Apart from these findings, no differences in the adverse event profile were observed in this group compared to younger patients in clinical trials.

Children

The effects of long-term (>36 weeks) gabapentin therapy on learning ability, intelligence, and development in children and adolescents have not been adequately studied. Therefore, the benefits of long-term therapy should be weighed against the potential risks of such therapy.

Abuse and addiction

There have been postmarketing reports of abuse and dependence. Patients should be carefully monitored for a history of drug abuse and for signs of potential abuse of gabapentin, such as drug-seeking, dose escalation, or tolerance.

Dose reduction, discontinuation of the drug or replacement with another (alternative) drug should be carried out gradually, over at least one week. Abrupt discontinuation of antiepileptic drug treatment in patients with epilepsy may provoke status epilepticus.

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

The use of alcohol and drugs may increase CNS side effects, such as confusion and ataxia.

When performing semi-quantitative determination of total protein in urine using rapid tests, false positive results may be obtained. Therefore, if necessary, it is recommended to conduct additional analyses using other methods (biuret method, turbidimetric method, dye tests) or use these methods first.

Excipients

The drug contains lactose. Patients with rare hereditary diseases, such as lactose intolerance, total lactase deficiency, glucose-galactose malabsorption should not take the drug.

Ability to influence reaction speed when driving vehicles or other mechanisms

Gabapentin may have minor or moderate influence on the ability to drive and use machines. Gabapentin acts on the central nervous system and may cause drowsiness, dizziness or other similar symptoms. Even if mild or moderate, these undesirable effects can be potentially dangerous for patients who drive or use machines, especially at the beginning of treatment and after increasing the dose.

Use during pregnancy or breastfeeding

Pregnancy

Risks associated with epilepsy and all anticonvulsant drugs

The risk of birth defects in children born to mothers who have received anticonvulsants is 2-3 times higher. The most frequently reported cases are cleft lip, cardiovascular malformations, and neural tube defects. Multiple antiepileptic therapy is associated with a higher risk of birth defects, so it is important to use monotherapy whenever possible. Women planning pregnancy and women of childbearing potential should be instructed that anticonvulsant therapy should be reviewed if pregnancy is planned. Anticonvulsant therapy should not be abruptly discontinued, as this may precipitate seizures, which can be serious for both the mother and the fetus. Developmental delay in children of mothers with epilepsy is rare. It is impossible to determine exactly how developmental delay in a child may be caused - genetic, social, maternal illness, or anticonvulsant therapy.

Risks associated with gabapentin therapy

Gabapentin crosses the placenta. There are no adequate data on the use of gabapentin in pregnant women.

Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

Therefore, gabapentin should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus. It is not possible to determine whether gabapentin is associated with an increased risk of congenital malformations when used during pregnancy, as both epilepsy and the use of antiepileptic drugs can cause such malformations during this period.

Breastfeeding period

Gabapentin is excreted in breast milk. Since its effects on breast-fed infants are unknown, caution should be exercised when gabapentin is administered to lactating women. Therefore, breast-feeding should be discontinued during treatment.

Fertility

No effects on fertility were observed in animal studies.

Method of administration and doses

For oral use.

Gabapentin can be taken with or without food; the capsules should be swallowed whole with a sufficient amount of water (e.g. 1 glass of water).

For all indications, a dose titration regimen at the beginning of therapy (described in Table 3) is recommended for adults and children aged 12 years and older.

Table 3

Dosage instructions for children under 12 years of age are provided in this section below.

Discontinuation of gabapentin therapy

Clinical data suggest that if gabapentin treatment needs to be discontinued, it should be done gradually over at least 1 week, regardless of the indication.

Epilepsy

Epilepsy usually requires long-term therapy. The dosage is determined by the doctor according to the individual tolerability of the drug and the effectiveness of the treatment.

Adults and children aged 12 and over

The effective dose range is 900 to 3600 mg per day.

Therapy may be initiated by titrating the dose as shown in Table 1 or by administering 300 mg 3 times daily on the first day. Thereafter, based on individual patient response and tolerability, the dose may be further increased by 300 mg/day every 2-3 days to a maximum dose of 3600 mg/day.

For individual patients, a slower titration of gabapentin may be appropriate. The minimum time to reach a dose of 1800 mg/day is 1 week, to reach a dose of 2400 mg/day is 2 weeks, and to reach a dose of 3600 mg/day is 3 weeks. There is evidence that doses up to 4800 mg/day have been well tolerated in long-term open-label clinical trials. The daily dose should be divided into 3 doses. The maximum interval between doses should not exceed 12 hours to prevent seizures.

The initial dose should be 10 to 15 mg/kg/day, and the effective dose is achieved by titrating the dose upwards over approximately 3 days. The effective dose of gabapentin for children aged 6 years and older is 25-35 mg/kg/day. There is evidence that a dose of 50 mg/kg body weight per day has been well tolerated in long-term studies. The total daily dose should be divided into 3 separate doses, the maximum interval between doses should not exceed 12 hours.

There is no need to monitor plasma concentrations. Gabapentin can subsequently be used in combination with other antiepileptic drugs without regard to changes in gabapentin plasma concentrations or serum concentrations of other antiepileptic drugs.

Peripheral neuropathic pain

Adults

Treatment may be initiated by titrating the dose as outlined in Table 1. Alternatively, the initial dose may be 900 mg/kg/day given in 3 divided doses. The dose may then be increased by 300 mg/day every 2-3 days based on individual patient response and tolerability to a maximum dose of 3600 mg/day. Some patients may require a slower titration of gabapentin. The minimum time to reach a dose of 1800 mg/day is 1 week, to reach 2400 mg/day is 2 weeks, and to reach 3600 mg/day is 3 weeks.

In the treatment of peripheral neuropathic pain, including painful diabetic neuropathy and postherpetic neuralgia, efficacy and safety have not been studied for treatment periods longer than 5 months. If a patient requires treatment for more than 5 months for peripheral neuropathic pain, the physician should assess the patient's clinical status and determine the need for additional therapy.

Instructions regarding prescriptions for all indications

For patients with weakened general health, with low body weight, after organ transplantation, the dose should be titrated more slowly, using either a dosage form with a lower dosage or increasing the intervals between dose increments.

Elderly patients (age over 65 years)

Elderly patients may require dose adjustment due to decreased renal function with age (see Table 2).

Elderly patients may commonly experience drowsiness, peripheral edema, and asthenia.

Kidney failure

Gabapentin dosage adjustments are required for patients with renal impairment (see Table 4) and patients on hemodialysis.

Table 4

Gabapentin doses in adults based on renal function

1) Total daily dose should be divided into 3 doses. Reduced dosage for patients with renal insufficiency (creatinine clearance < 79 ml/min).

2) 300 mg should be administered every other day.

3) For patients with creatinine clearance < 15 ml/min, the daily dose should be reduced in proportion to the creatinine clearance (e.g., patients with creatinine clearance 7.5 ml/min should receive half the daily dose of patients with creatinine clearance 15 ml/min).

Use in patients undergoing hemodialysis

For anuric patients on hemodialysis who have never received gabapentin before, a loading dose of 300 to 400 mg is recommended, followed by 200-300 mg of gabapentin after each 4-hour hemodialysis session. Gabapentin should not be taken on non-dialysis days. For patients with renal impairment on hemodialysis, the maintenance dose of gabapentin should be established according to the dosage recommendations in Table 2. In addition to the maintenance dose, 200-300 mg of the drug is recommended after each 4-hour hemodialysis session.

Children

Gabapentin is indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalization in children aged 6 years and older. Gabapentin is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalization in children aged 12 years and older.

Overdose

Acute life-threatening toxicity has not been observed with gabapentin overdose in doses up to 49 g. Symptoms of overdose are increased manifestations of side effects (dizziness, ataxia, diplopia, slurred speech, dysarthria, drowsiness, lethargy, apathy, mild diarrhea).

All patients recovered completely after treatment. The reduced absorption of gabapentin at higher doses may limit the absorption of the drug in overdose, and therefore minimize the toxicity caused by overdose.

Overdose of gabapentin, especially in combination with other CNS depressants, may lead to coma.

Treatment. Symptomatic therapy. Gabapentin can be removed from the circulation by hemodialysis. However, experience shows that this is not necessary. However, hemodialysis may be effective for patients with severe renal insufficiency.

In animal studies, oral administration of gabapentin at a dose of 8 g/kg did not result in a lethal dose. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, decreased activity, or agitation.

Adverse reactions

Adverse reactions observed in clinical trials for the treatment of epilepsy (the drug was used both as monotherapy and in combination therapy) and neuropathic pain are presented in the table below: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000). Adverse reactions that occurred in different studies with different frequencies are presented in the group with the highest frequency that occurred. Additional undesirable effects reported in post-marketing studies are listed in the category "not known" (cannot be estimated from the available data) and are highlighted in italics.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 5

Adverse reactions

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")

Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia, drug eruptions with eosinophilia and systemic symptoms (see section "Special warnings and precautions for use")

Cases of acute pancreatitis have been reported with gabapentin treatment. A causal relationship to gabapentin has not been established.

There have been reports of myopathy with elevated creatinine levels in patients on hemodialysis with end-stage renal failure.

There is evidence that respiratory infections, middle ear infections, bronchitis, and seizures were observed only in children, and the occurrence of aggressive behavior and hyperkinesias in children was also frequently reported.

Expiration date

5 years.

Storage conditions

Store out of the reach of children at a temperature not exceeding 30 ºС.

Packaging

100 capsules in bottles.

Vacation category

According to the recipe.

Producer

Pharmascience Inc.

Location of the manufacturer and its business address

6111 100 Royalmount Avenue, Montreal, Quebec H4R 2T4, Canada.