Gabagamma, 400 mg capsules 20 pcs

Seizures, Epilepsy

Indications

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.
Monotherapy for partial seizures with or without secondary generalization in adults and children over 12 years of age.
Efficacy and safety 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 over 3 years of age. Efficacy and safety in children under 3 years of age have not been established.

Pharmacological effect

Pharmacological action – anticonvulsant.

Pharmacodynamics

The exact mechanism of action of gabapentin is unknown. The chemical structure of gabapentin is similar to that of the neurotransmitter gamma-aminobutyric acid (GABA), but its mechanism of action differs from other drugs that interact with GABA receptors (valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA reuptake inhibitors, GABA agonists and GABA prodrugs).

In vitro studies with radiolabeled gabapentin in the rat brain revealed new areas of drug binding to proteins, including. neocortex and hippocampus, which may be related to the anticonvulsant and analgesic activity of gabapentin and its derivatives. Preliminary studies have shown that gabapentin binds to the α2,δ subunit of voltage-gated calcium channels and reduces the flow of calcium ions, which plays an important role in neuropathic pain.

At clinically significant concentrations, gabapentin does not bind to other common drug and neurotransmitter receptors present in the brain, incl. GABAA, GABAB, benzodiazepine, glutamate, glycine and N-methyl-d-aspartate receptors.

Unlike phenytoin and carbamazepine, gabapentin does not interact with sodium channels in vitro. In vitro use of gabapentin results in negligible release of monoamine neurotransmitters. Administration of gabapentin to rats increased the rate of GABA metabolism in some brain regions, similar to the effect of sodium valproate, but the effect was observed in other brain regions. The connection between the described effects of gabapentin and its anticonvulsant activity has not currently been established.

In animals, gabapentin easily penetrates into the brain tissue and prevents convulsions provoked by maximum electric shock, chemical convulsants, incl. inhibitors of GABA synthesis, as well as in the case of genetic models of convulsive syndromes.

Clinical trials 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 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 of 3–5 and 6–12 years) did not reveal a statistically significant effect of age on the effectiveness of therapy.

Pharmacokinetics

The bioavailability of gabapentin is not proportional to dose. So, as the dose increases, it decreases. After oral administration, the Cmax of gabapentin in plasma is achieved within 2–3 hours. The absolute bioavailability of gabapentin when taking capsules at a dosage of 300 mg is about 60%. Food, incl. with a high fat content, does not have a significant effect on pharmacokinetics. Pharmacokinetics do not change with repeated use; Steady-state plasma concentrations can be predicted from the results of a single dose of the drug.

Distribution. Gabapentin practically does not bind to plasma proteins (<3%) and has a Vd of 57.7 l. In patients with epilepsy, the concentration of gabapentin in the cerebrospinal fluid is approximately 20% of the minimum Css in blood plasma. Gabapentin is excreted into breast milk.

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

Excretion. It is excreted exclusively by the kidneys unchanged and is not metabolized. T1/2 from plasma does not depend on the dose and averages 5–7 hours.

Plasma clearance of gabapentin is reduced in the elderly and patients with impaired renal function. The elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine Cl. Gabapentin is removed from plasma during hemodialysis. In patients with impaired renal function and patients receiving hemodialysis treatment, dose adjustment is recommended (see “Dosage and Administration”).

Pharmacokinetics 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 aged 1 to 48 months, AUC was approximately 30% lower, Cmax was lower, and clearance was higher per unit body weight compared with available published kinetic data in children over 5 years of age.

Linearity/nonlinearity of pharmacokinetic parameters. The bioavailability of gabapentin decreases with increasing dose, which entails nonlinearity of the pharmacokinetic parameters, which are included in the calculation of the bioavailability indicator. Elimination pharmacokinetics are better described by a linear model. Css of gabapentin in blood plasma are predictable based on single-dose kinetic data.

Special instructions

Suicide, suicidal thoughts or worsening clinical picture. Suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs for several indications, including gabapentin. 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 of this risk is unknown, and available data do not exclude the possibility of an increased risk with gabapentin use. Patients should be closely monitored to identify suicidal thoughts and behavior. When these signs appear, appropriate treatment must be prescribed. Patients and caregivers should be advised to 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.

Anaphylaxis. Gabapentin may cause anaphylaxis. The following signs and symptoms have been recorded: difficulty breathing, swelling of the lips, throat, tongue, hypotension, requiring immediate treatment. Patients should stop taking the drug and consult a doctor at the first sign.

Drug rash with eosinophilia and systemic manifestations (DRESS syndrome). Severe life-threatening systemic hypersensitivity reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS syndrome), have been reported in patients taking antiepileptic drugs, including gabapentin. It should be noted that early manifestations of hypersensitivity, such as fever or swollen lymph nodes (lymphadenopathy), may occur even if there is no rash. If such signs or symptoms occur, the patient should be evaluated immediately. Gabapentin should be discontinued unless an alternative cause for these symptoms can be identified.

Convulsions (withdrawal syndrome). Although withdrawal syndrome has not been observed with gabapentin treatment, it is not recommended to abruptly stop treatment. Withdrawal of any anticonvulsants in patients with epilepsy can provoke status epilepticus. As with other anticonvulsants, attempts to discontinue all concomitant antiepileptic drugs and initiate gabapentin monotherapy in cases of refractory treatment in patients taking multiple drugs are generally unsuccessful. When treated with gabapentin, as with other anticonvulsants, some patients may experience an increase in the frequency of seizures or the appearance of new types of seizures.

Gabapentin monotherapy in the treatment of patients resistant to anticonvulsant therapy is not successful, as is the case with other antiepileptic drugs. Gabapentin is not effective for primary generalized seizures, such as absence seizures, and may worsen these seizures in some patients. Gabapentin should be used with caution in patients with mixed seizures, including absence epilepsy.

Patients 65 years of age and older. No systematic studies have been conducted with gabapentin in patients 65 years of age and older. In a double-blind study, patients with neuropathic pain aged 65 years and older were shown to have drowsiness, peripheral edema, and asthenia at a slightly higher percentage than younger individuals. Along with these observations, clinical studies in this age group do not indicate that the adverse event profile differs from that observed in younger patients.

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

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).

Laboratory research. When gabapentin is added to other anticonvulsants, false-positive results have been reported with urinary protein testing using AmesN-MultistixSG® 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 use caution until they know the possible effects of this drug. When used simultaneously with opioid analgesics, an increase in gabapentin in blood plasma may be observed. Therefore, 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.

Combined use with antacids. It is recommended to take gabapentin approximately 2 hours after taking the antacid. Gabagamma® contains lactose. The drug is contraindicated in patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Impact on the ability to drive vehicles and machinery. While taking the drug, it is not recommended to drive vehicles or use potentially dangerous equipment until it is confirmed that there is no negative impact on the performance of these functions.

Gabapentin affects the central nervous system and may cause dizziness, drowsiness, confusion, loss of consciousness, and other central nervous system symptoms. Even if they are mild or moderate in severity, these adverse reactions can pose a danger to patients driving vehicles or operating machinery. This likelihood is especially high at the beginning of treatment or after increasing the dose of the drug.

Active ingredient

Gabapentin

Composition

Active ingredient: gabapentin 400 mg;

Excipients: lactose, corn starch, talc, gelatin, titanium dioxide, iron oxide yellow, iron oxide red.

Pregnancy

Risk associated with epilepsy and antiepileptic drugs in general. Mothers receiving antiepileptic drugs have a 2-3 times increased risk of having children with birth defects. The most frequently reported cases of children being born with cleft lip and palate, CVS malformations, and neural tube defects. Combination therapy with several antiepileptic drugs increases the risk of congenital malformations to a greater extent than monotherapy.

Therefore, monotherapy should be preferred whenever possible. Women of childbearing age who require anticonvulsant therapy should consult a specialist. The need to continue treatment with anticonvulsants should be reconsidered if pregnancy is planned. You should not abruptly discontinue antiepileptic drugs, because this may lead to a recurrence of seizures, which can have serious consequences for the health of the mother and baby.

Developmental delays in children born to women with epilepsy are rare. It is not possible to differentiate what causes developmental delay: genetic, social factors, maternal disease with epilepsy, or the use of antiepileptic drugs.

Risks associated with gabapentin use. There are no data on the use of gabapentin in pregnant women. Reproductive toxicity has been shown in animal studies. The potential risk to humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus.

No definitive conclusions can be drawn as to whether there is an increased risk of congenital malformations if gabapentin is used during pregnancy because every report of gabapentin use in pregnancy involved epilepsy per se and concomitant antiepileptic drug therapy.

Gabapentin passes into mother’s milk. Because the effect of gabapentin on breast-fed infants is unknown, caution should be exercised when prescribing gabapentin to a mother while breastfeeding. Gabagamma® should be used in nursing mothers only if the potential benefit to the mother outweighs the potential risk to the fetus.

In animal studies, there was no effect of gabapentin on fertility.

Contraindications

Hypersensitivity to any of the components of the drug, lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Use as monotherapy for partial seizures with secondary generalization in children under 12 years of age.

As an additional agent in the treatment of partial seizures with and without secondary generalization in children under 3 years of age.

Treatment of neuropathic pain in children and adolescents under 18 years of age.

With caution

Renal failure (see “Dosage and Administration”).

Side Effects

The frequency of side effects noted during clinical trials conducted in patients suffering from epilepsy (in combination therapy and in monotherapy) and in patients with neuropathic pain is distributed in the following order: very often (more than 10% of cases), often (in 1–10% of cases), infrequently (in 0.1–1% of cases), rarely (in 0.01–0.1% of cases), very rarely (<0.01% of cases), including reports of isolated side effects effects. Where different frequencies of side effects were noted, the highest frequency is indicated.

For adverse reactions noted in post-marketing surveillance, the frequency cannot be estimated based on the available data (their frequency is indicated in the table as “frequency unknown”). Within each group, adverse effects are presented in descending order of severity.

Infections and parasitic diseases: very often – viral diseases; often – pneumonia, respiratory tract infection, urinary tract infection, other infections, otitis media.

From the blood and lymphatic system: often – leukopenia; frequency unknown – thrombocytopenia.

From the immune system: infrequently – allergic reactions (including urticarial rash); frequency unknown – hypersensitivity syndrome, including systemic reactions such as fever, rash, hepatitis, lymphadenopathy, eosinophilia, anaphylaxis.

Metabolism and nutrition: often – anorexia, increased appetite.

Mental disorders: often – hostility, confusion, emotional lability, depression, anxiety, increased nervous excitability, thinking disorders; infrequently – deterioration of mental state, anxiety; frequency unknown – hallucinations.

From the nervous system: very often – drowsiness, dizziness, ataxia; often – convulsions, hyperkinesis, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances such as paresthesia, decreased sensitivity, impaired coordination of movements, nystagmus, increased, decreased or absent reflexes; infrequently – hypokinesia, decreased cognitive function; rarely – loss of consciousness; frequency unknown – other motor dysfunctions (including choreoathetosis, dyskinesia, dystonia).

From the organ of vision: often – visual impairment, such as amblyopia, double vision.

From the organ of hearing and labyrinthine disorders: often – dizziness; frequency unknown – ringing in the ears.

From the side of the heart: infrequently – palpitations.

Vascular disorders: often – hypertension, vasodilation.

From the respiratory system, chest and mediastinal organs: often – shortness of breath, bronchitis, pharyngitis, cough, rhinitis.

From the gastrointestinal tract: often – nausea, vomiting, dental problems, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth and throat, flatulence; frequency unknown – pancreatitis.

From the liver and biliary tract: frequency unknown – hepatitis, jaundice.

From the skin and subcutaneous tissue: often – swelling of the face, hemorrhagic rash, most often described as bruises as a result of physical trauma, rash, itching, acne; frequency unknown – drug rash with eosinophilia and systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia.

From the musculoskeletal system and connective tissue: often – joint pain, muscle pain, back pain, convulsive twitching; frequency unknown – myoclonus, rhabdomyolysis.

From the kidneys and urinary tract: frequency unknown – acute renal failure, urinary incontinence.

From the genital organs and mammary gland: often – impotence; frequency unknown – breast hypertrophy, gynecomastia, sexual dysfunction (changes in libido, impaired ejaculation and anorgasmia).

General disorders and disorders at the injection site: very often – fatigue, fever; often – peripheral edema, gait disturbances, asthenia, pain of various localizations, malaise, flu-like syndrome; infrequently – generalized edema; frequency unknown – withdrawal syndrome, which manifests itself in the form of anxiety, insomnia, nausea, sweating, chest pain. Cases of sudden death have been reported, but a causal relationship with gabapentin treatment has not been established.

Laboratory and instrumental data: often – decreased levels of leukocytes in the blood, increased body weight; uncommon – increased concentrations of liver enzymes (AST, ALT) and bilirubin, hyperglycemia (most often observed in patients with diabetes mellitus); rarely – hypoglycemia (most often observed in patients with diabetes mellitus); frequency unknown – increased CPK activity, hyponatremia.

Injuries, intoxications and complications of manipulations: often – accidental injury, fracture, abrasions; infrequently – falls.

Cases of acute pancreatitis have been reported during treatment with gabapentin. A cause-and-effect relationship with gabapentin has not been established. Cases of myopathy with increased creatine kinase activity have been reported in patients with end-stage renal disease undergoing hemodialysis. Respiratory tract infections, otitis media, bronchitis and convulsions in children have only been reported in clinical studies. In addition, hyperkinesia and aggressive behavior were often observed in children in clinical studies.

Interaction

There are reports of spontaneous cases, as well as information from the literature, about possible respiratory depression and/or symptoms of sedation associated with gabapentin and opioid analgesics. When gabapentin 600 mg was administered 2 hours after morphine 60 mg controlled-release capsules, there was a 44% increase in mean gabapentin AUC compared with that without morphine, which was associated with an increase in pain threshold (cold pressor test).

The clinical significance of this change has not been established; the pharmacokinetic characteristics of morphine did not change. The side effects of morphine when taken together with gabapentin did not differ from those when morphine was taken together with placebo. The extent to which these drugs interact at other doses is unknown. Careful monitoring of such patients is necessary.

No interactions were observed between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine. The pharmacokinetics of gabapentin at steady state are the same for healthy individuals and patients with epilepsy receiving other anticonvulsants.

The simultaneous use of gabapentin and oral contraceptives containing norethisterone and/or ethinyl estradiol does not affect the pharmacokinetics of both components.

With simultaneous use of gabapentin with antacids containing aluminum and magnesium, the bioavailability of gabapentin is reduced by 24%. It is recommended to take gabapentin approximately 2 hours after taking antacids. When taking probenecid, the renal excretion of gabapentin does not change.

When taken together with cimetidine, a slight decrease in the renal excretion of gabapentin is observed, which has no clinical significance.

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

Symptoms (with a single dose of 49 g of gabapentin): dizziness, diplopia, speech impairment, drowsiness, lethargy, lethargy, loss of consciousness, diarrhea. It should be taken into account that when taking high doses of gabapentin, its absorption in the intestine decreases. In case of an overdose of gabapentin, coma may develop, especially when used simultaneously with other drugs that depress the central nervous system. Although gabapentin can be eliminated by hemodialysis, current experience shows that this is not usually necessary.

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.

Treatment: gastric lavage, administration of activated carbon, symptomatic therapy. Hemodialysis may be indicated for patients with severe renal failure.

Storage conditions

At a temperature not higher than 25°C.

Keep out of the reach of children.

Shelf life

3 years. Do not use the drug after the date indicated on the package.

Manufacturer

Dragenopharm Apotheker Püschl GmbH, Germany