Neurontin, 600 mg 100 pcs

Seizures, Epilepsy, Pain

• Treatment of neuropathic pain in adults 18 years and older;
• monotherapy of partial seizures with and without secondary generalization in adults and children over 12 years;
• as an adjunctive treatment for partial seizures with and without secondary generalization in adults and children 3 years and older.

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Indications

Epilepsy

Monotherapy for partial seizures with and without secondary generalization in adults and children aged 12 years and older. The effectiveness and safety of monotherapy in children under 12 years of age have not been established.
As an additional remedy in the treatment of partial seizures with and without secondary generalization in adults and children aged 3 years and older. The safety and effectiveness of adjunctive gabapentin therapy in children less than 3 years of age have not been established.

Neuropathic pain

Treatment of neuropathic pain in adults aged 18 years and older. Efficacy and safety in patients under 18 years of age have not been established.

Pharmacological effect

Mechanism of action
Gabapentin readily penetrates brain tissue and prevents the development of seizures in various animal models of epilepsy. Gabapentin has no affinity for the GABAA (gamma-aminobutyric acid) and GABAB receptors and does not affect the metabolism of GABA. Gabapentin does not bind to the receptors of other neurotransmitters present in the brain and does not affect sodium channels.
Gabapentin has high affinity and binds to the α-2-δ (alpha-2-delta) subunit of voltage-gated calcium channels, and gabapentin binding to the α-2-δ subunit has been suggested to be involved in the mechanism of its anticonvulsant effect in animals. Screening of a large group of target molecules for this drug showed that the only target for it is the α2δ subunit.
Results obtained in several preclinical models indicate that the pharmacological activity of gabapentin may be exerted by binding to the α2δ subunit by inhibiting the release of excitatory neurotransmitters in certain areas of the central nervous system. This activity may underlie the anticonvulsant action of gabapentin. The relevance of these mechanisms of action of gabapentin to its anticonvulsant effects in humans still needs to be established. The effectiveness of gabapentin has also been shown in several preclinical studies in animal models of pain. It has been suggested that gabapentin’s specific binding to the α2δ subunit results in several distinct effects that may be responsible for its analgesic effects in animal models. The analgesic effect of gabapentin can manifest itself at the level of the spinal cord, as well as at the level of higher brain centers through interactions with descending pathways that suppress the transmission of pain impulses. The significance of these properties of gabapentin observed in preclinical studies is unknown.
Clinical efficacy and safety
A clinical trial of adjuvant treatment of partial-onset seizures in children aged 3 to 12 years demonstrated a quantitative but non-significant difference in the rate of seizure reduction of more than 50% in the gabapentin group compared with the placebo group. Additional analysis of the response rate to therapy depending on age (when considering age as a continuous variable or when distinguishing two age subgroups: 3 – 5 years and 6 – 12 years) did not reveal a statistically significant effect of age on the effectiveness of therapy.
The results of this additional analysis are presented in the table below.
Response (50% reduction in seizure frequency) by treatment and age, MITT population*
Age group: < 6 years
Placebo: 4/21 (19.0%)
Gabapentin: 4/17 (23.5%)
P-value: 0.7362
Age group: 6 – 12 years old
Placebo: 17/99 (17.2%)
Gabapentin: 20/96 (20.8%)
P-value: 0.5144
*The modified intention-to-treat (MITT) population was defined as all patients randomized to study treatment and with evaluable seizure diaries over the period
lasting 28 days during the baseline and double-blind phases of the study.

Suction
After oral administration, the maximum concentration of gabapentin in the blood plasma is achieved within 2 to 3 hours. The bioavailability of gabapentin tends to decrease with increasing dosage of the drug. Absolute bioavailability when taking 300 mg capsules is approximately 60%. Food, including food high in fat, does not have a clinically significant effect on the pharmacokinetic parameters of gabapentin.
The pharmacokinetics of gabapentin does not change with repeated administration of the drug. Although gabapentin plasma concentrations typically ranged from 2 mcg/mL to 20 mcg/mL in clinical studies, they did not predict either the efficacy or safety of the drug. Pharmacokinetic parameters are presented in the table.
Table – Summary of average (CV, %) parameters of the pharmacokinetics of gabapentin at steady state during repeated dosing with a dosing interval of eight hours
300 mg (N=7)
Cmax (µg/ml): Average – 4.02, % CV – (24)
tmax (h): Average – 2.7, % CV – (18)
T1/2 (h): Average – 5.2, % CV – (12)
AUC (0-8) (mcg*h/ml): Average – 24.8, % CV – (24)
Ae% (%): Average – No data available, % CV – No data available
400 mg (N=14)
Cmax (µg/ml): Average – 5.74, %CV – (38)
tmax (h): Average – 2.1, % CV – (54)
T1/2 (h): Average – 10.8, % CV – (89)
AUC (0-8) (mcg*h/ml): Average – 34.5, % CV – (34)
Ae% (%): Average – 47.2, % CV – (25)
800 mg (N=14)
Cmax (µg/ml): Average – 8.71, % CV – (29)
tmax (h): Average – 1.6, % CV – (76)
T1/2 (h): Average – 10.6, % CV – (41)
AUC (0-8) (µg*h/ml): Average – 51.4, % CV – (27)
Ae% (%): Average – 34.4, % CV – (37)
Cmax is the maximum concentration in blood plasma in a state of stable equilibrium.
tmax – time to reach Cmax.
T1/2 – half-life.
AUC(0-8) is the area under the plasma concentration versus time curve at steady state in the period from 0 to 8 hours after taking the drug.
Ae% – the proportion of the drug eliminated in the urine unchanged during the period from 0 to 8 hours after taking the drug, as a percentage of the dose taken.
Distribution
Gabapentin does not bind to plasma proteins and its volume of distribution is 57.7 L. In patients with epilepsy, the concentration of gabapentin in the cerebrospinal fluid (CSF) is approximately 20% of the minimum steady-state plasma concentration. Gabapentin is excreted into breast milk.
Biotransformation
There are no data on the metabolism of gabapentin in humans. Gabapentin does not induce nonspecific liver oxidases responsible for drug metabolism.
Removal
Gabapentin is eliminated unchanged exclusively by renal excretion. The half-life of gabapentin does not depend on the dose taken and averages from 5 to 7 hours.
In elderly people and patients with impaired renal function, the clearance of gabapentin from blood plasma is reduced. The elimination constant, plasma clearance and renal clearance of gabapentin are directly proportional to creatinine clearance.
Gabapentin is removed from blood plasma during hemodialysis. For patients with impaired renal function or those on hemodialysis, a dose adjustment of the drug is recommended (see section “Method of administration and dosage”).
The pharmacokinetics of gabapentin in children was studied in 50 healthy volunteers aged 1 month to 12 years. In general, the concentration of gabapentin in the blood plasma of children over 5 years of age is similar to that in adults when using the drug in an equivalent dose based on the calculation of mg/kg body weight.
In a pharmacokinetic study in 24 healthy children 1 to 48 months of age, drug exposure (AUC) was approximately 30% lower, Cmax was lower, and clearance per unit body weight was higher compared to available published drug kinetic data in children over 5 years of age.
Linearity/nonlinearity of pharmacokinetic parameters
The bioavailability of gabapentin decreases with increasing dose, which entails non-linearity of pharmacokinetic parameters, which include the bioavailability index (F) in the calculation, for example Ae%, CL/F, Vd/F. Elimination pharmacokinetics (non-F parameter parameters such as CLr and T1/2) are better described by a linear model. Steady-state plasma concentrations of gabapentin are predictable based on single-dose kinetic data.

Special instructions

Suicidal ideation and behavior
Suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs for several 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 by which this risk increases is unknown.
Cases of suicidal thoughts and behavior have been observed in patients treated with gabapentin during post-marketing use (see section “Side effects”).
Patients (and caregivers) should seek medical attention if signs of suicidal thoughts or behavior occur.
Patients receiving these drugs should be closely monitored for signs of suicidal ideation and behavior, and appropriate treatment should be considered. If suicidal thoughts and behavior occur, discontinuation of gabapentin therapy should be considered.
Acute pancreatitis
If acute pancreatitis develops while taking gabapentin, the possibility of discontinuing the drug should be assessed.
Convulsions (withdrawal syndrome)
Although withdrawal syndrome accompanied by the development of seizures has not been observed during treatment with gabapentin, abrupt cessation of anticonvulsant drug therapy in patients with epilepsy may provoke the development of status epilepticus (see section “Dosage and Administration”).
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.
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 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 when prescribing long-term therapy should be assessed.
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, physicians 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).
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 nabapentine – 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 method of precipitation with 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 know the possible effects of this drug.
Concomitant use of opioid analgesics and other drugs that depress the central nervous system
When used simultaneously with opioid analgesics, an increase in the concentration of gabapentin in the blood plasma may be observed. Therefore, patients who require concomitant therapy with CNS depressant drugs, including opioid analgesics, should be closely monitored for signs of central nervous system (CNS) depression, such as somnolence, sedation, and respiratory depression. Doses of gabapentin or concomitantly used CNS depressants, including opioid analgesics, should be reduced accordingly (see Interactions with Other Drugs).
Caution should be exercised when prescribing gabapentin concomitantly with opioids due to the risk of CNS depression. In a population-based observational study using a control group in patients taking opioids, concomitant use of opioids and gabapentin was associated with an increased risk of opioid-related deaths compared with use of opioids alone (adjusted odds ratio [aOR], 1.49 [95% CI, 1.18 to 1.88, p < 0.001]).
Combined use with antacids
Gabapentin is recommended to be taken approximately 2 hours after taking the antacid.

Active ingredient

Gabapentin

Composition

1 tablet 600 mg contains:

Active ingredient: 600.0 mg gabapentin.

Excipients: poloxamer 407 80.0 mg, copovidone 64.8 mg, corn starch 49.2 mg, magnesium stearate 6.0 mg;

film coating: opadry white YS-1-18111 24.0 mg, herbal wax (candelilla) 0.6 mg.

Pregnancy

Pregnancy
General risk associated with epilepsy and antiepileptic drugs
The risk of having children with congenital anomalies in mothers who are treated with anticonvulsants increases 2-3 times. Most often, cleft lip and palate, malformations of the cardiovascular system and neural tube defects are observed. However, taking multiple anticonvulsants may be associated with a greater risk of malformations than in the case of monotherapy. Therefore, if possible, one of the anticonvulsants should be used. Women of childbearing age, and all women who may become pregnant, should seek advice from a qualified healthcare professional. If a woman is planning a pregnancy, the need to continue anticonvulsant therapy should be re-evaluated. However, anticonvulsant drugs should not be discontinued abruptly, as this can lead to resumption of seizures with serious consequences for the mother and child. In rare cases, developmental delays have been observed in children whose mothers have epilepsy. However, it is impossible to determine whether developmental delay is associated with genetic or social factors, maternal illness or
anticonvulsant therapy.
Risk associated with gabapentin
Gabapentin crosses the placenta. Congenital malformations and adverse pregnancy outcomes have been reported with the use of gabapentin, however, there are no adequate controlled studies of the drug in pregnant women, and it is not possible to definitively conclude that gabapentin is associated with an increased risk of congenital anomalies or other adverse developmental outcomes when used during pregnancy due to the presence of epilepsy itself and concomitant use of other antiepileptic drugs in every reported case. Experiments on animals showed the toxicity of the drug to the fetus. The potential risk to humans is unknown. Therefore, gabapentin should be used during pregnancy only if the expected benefit to the mother justifies the possible risk to the fetus.
Breastfeeding
Gabapentin is excreted in breast milk and its effect on the nursing infant is unknown, so Neurontin should only be prescribed during breastfeeding if the benefit to the mother clearly outweighs the risk to the infant.
Fertility
There was no effect of gabapentin on fertility in animal studies.

Contraindications

Hypersensitivity to gabapentin or auxiliary components of the drug.

Side Effects

Adverse reactions observed in clinical studies in patients with epilepsy (using gabapentin as monotherapy or in combination with other anticonvulsants) or neuropathic pain are presented below and categorized by organ system and frequency.
The frequency category was defined as follows: very often (≥1/10); often (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10000 to <1/1000); very rare (< 1/10000).
If the frequency category was different between studies, the adverse reaction was assigned a higher category.
Adverse reactions reported during the use of the drug after registration were assigned a frequency category of “unknown” (frequency cannot be calculated based on available data).
In each frequency section, adverse reactions are presented in order of decreasing severity.
Infectious and parasitic diseases: very often – viral infections; often – pneumonia, respiratory tract infection, urinary tract infection, other types of infection, otitis media.
Disorders of the blood and lymphatic system: often – leukopenia; unknown – thrombocytopenia.
Immune system disorders: uncommon – allergic reactions, including urticaria; unknown – hypersensitivity, including systemic reactions such as fever, rash, hepatitis, lymphadenopathy, eosinophilia and others.
Metabolic and nutritional disorders: often – anorexia, increased appetite.
Mental disorders: often – hostility, confusion, depression, anxiety, nervousness; infrequently – deterioration of mental state; unknown – suicidal thoughts, hallucinations.
Nervous system disorders: very often – drowsiness, dizziness, ataxia; often – convulsions, hyperkinesia, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances (for example, paresthesia, hypesthesia), loss of coordination, nystagmus, strengthening, weakening or absence of reflexes; infrequently – hypokinesia; rarely – loss of consciousness; unknown – other movement disorders (eg, choreoathetosis, dyskinesia and dystonia).
Visual disorders: often – visual impairment (such as amblyopia, diplopia).
Hearing disorders and labyrinthine disorders: often – vertigo, unknown – tinnitus.
Cardiac disorders: uncommon – palpitations.
Vascular disorders: often – symptoms of vasodilation or arterial hypertension.
Disorders of the respiratory system, chest and mediastinal organs: often – shortness of breath, bronchitis, pharyngitis, cough, rhinitis.
Gastrointestinal disorders: often – constipation, diarrhea, dry mucous membrane of the mouth or pharynx, dyspepsia, flatulence, nausea, vomiting, abdominal pain, dental disease, gingivitis; unknown – pancreatitis.
Disorders of the liver and biliary tract: unknown – hepatitis, jaundice.
Skin and subcutaneous disorders: often – swelling of the face, purpura (most often described as bruising resulting from physical trauma), skin rash, acne, skin itching; unknown – Stevens-Johnson syndrome, angioedema, anaphylaxis, erythema multiforme, alopecia, drug skin rash, including eosinophilia and systemic reactions (see section “Special instructions”).
Musculoskeletal and connective tissue disorders: often – myalgia, arthralgia, back pain, muscle twitching; unknown – rhabdomyolysis, myoclonus. Renal and urinary tract disorders: unknown – urinary incontinence, acute renal failure.
Disorders of the genital organs and mammary gland: often – impotence; unknown – increase in the volume of the mammary glands, gynecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia).
General disorders and disorders at the injection site: very often – fatigue, fever; often – peripheral edema, gait disturbance, asthenia, pain of various localizations, general malaise, flu-like syndrome; infrequently – generalized edema; unknown – withdrawal syndrome (the most frequently reported adverse reactions were anxiety, insomnia, nausea, pain of various localizations and increased sweating), chest pain. There have been cases of sudden unexplained death, the connection of which with gabapentin treatment has not been established.
Laboratory and instrumental data: often – decreased concentration of white blood cells, increased body weight; infrequently – increased activity of alanine aminotransferase, aspartate aminotransferase and bilirubin concentration in the blood plasma, hyperglycemia; rarely – hypoglycemia (mainly in patients with diabetes mellitus); unknown – hyponatremia, increased creatine phosphokinase activity. Injuries, intoxications and complications of manipulations: often – injuries, fractures, abrasions associated with falls.
There are reports of the development of acute pancreatitis during therapy with gabapentin.
The causal relationship with gabapentin remains unclear (see section “Special instructions”).
There are reports of cases of myopathy with increased creatine kinase activity in patients with end-stage renal failure undergoing hemodialysis. Cases of respiratory tract infection, otitis media, bronchitis and seizures were reported only in clinical studies. In addition, clinical studies have reported cases of aggressive behavior and hyperkinesis in children.

Interaction

There have been spontaneous case reports and literature reports that respiratory depression, symptoms of sedation, and death may be associated with gabapentin when coadministered with CNS depressants, including opioid analgesics. In some of these cases, the authors considered that the concomitant use of gabapentin with opioids is a particular problem in frail patients, in elderly patients, in patients with serious underlying respiratory conditions, in patients who are co-prescribed multiple medications, and in patients who abuse substances.
In a study of healthy volunteers (N=12), administration of 600 mg gabapentin 2 hours after administration of morphine 60 mg extended-release capsules resulted in a 44% increase in mean gabapentin AUC compared to gabapentin monotherapy. Therefore, patients requiring concomitant therapy with opioid analgesics should be closely monitored for signs of central nervous system depression, such as somnolence, sedation, and respiratory depression, and the dosage of gabapentin and opioid analgesics should be reduced accordingly.
No interactions were observed between gabapentin and phenobarbital, phenytoin, valproic acid and carbamazepine. The pharmacokinetics of gabapentin at steady state are similar in healthy subjects and patients receiving other anticonvulsants. Concomitant use of gabapentin with oral contraceptives containing norethisterone and/or ethinyl estradiol is not accompanied by changes in the pharmacokinetics of both components.
The simultaneous use of gabapentin with antacids containing aluminum and magnesium is accompanied by a decrease in the bioavailability of gabapentin by approximately 24% (see section “Special instructions”).
Probenecid does not affect the renal excretion of gabapentin.
The small decrease (14%) in renal excretion of gabapentin with concomitant use of cimetidine is probably not clinically significant.
With simultaneous use of naproxen (250 mg) and gabapentin (125 mg), an increase in gabapentin absorption from 12% to 15% was observed. Gabapentin has no effect on the pharmacokinetic parameters of naproxen. The indicated doses of drugs are less than the minimum therapeutic ones. The simultaneous use of these drugs in large doses has not been studied.

Overdose

With a single dose of 49 g of gabapentin, the following symptoms were observed:
dizziness, double vision, speech impairment, drowsiness, loss of consciousness, lethargy and mild diarrhea, which completely disappeared with symptomatic therapy. It should be taken into account that after taking high doses of gabapentin, its absorption in the intestine decreases.
In case of an overdose of gabapentin, coma may develop, especially with the simultaneous use of other drugs that suppress the central nervous system.
Although gabapentin can be eliminated by hemodialysis, current experience shows that this is not usually necessary. Hemodialysis may be indicated for patients with severe renal impairment.
In experiments on mice and rats, to which the drug was administered in doses of up to 8000 mg/kg, it was not possible to establish the lethal dose of gabapentin when administered orally. Signs of acute toxicity in animals included ataxia, difficulty breathing, ptosis, hypoactivity or agitation.

Storage conditions

At a temperature not exceeding 25 °C.
Keep out of the reach of children.

Shelf life

2 years.
Do not use after the expiration date.

Manufacturer

Pfizer Pharmaceuticals LLC, Puerto Rico