Gabapentin - instructions for use, dose, side effects, contraindications

Excipients: calcium stearate 4.2 mg, sodium carboxymethyl starch type A 4.2 mg, microcrystalline cellulose 111.6 mg; Hard gelatin capsules No. 0 (composition of capsules: titanium dioxide 2%, gelatin up to 100%).

Description:Hard gelatin capsules № 0 of white color. The contents of the capsules are white or white with a yellowish tinge powder.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.X.12 Gabapentin

Pharmacodynamics:

Pharmacodynamics

The exact mechanism of action of gabapentin is not known.

The chemical structure of gabapentin is similar to the structure of the GABA (gamma-aminobutyric acid) neurotransmitter, but its mechanism of action differs from other active substances interacting with GABA synapses, such as valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA reuptake inhibitors, GABA agonists and prodrugs of GABA.

In studies in vitro with labeled radioisotope gabapentin in the brain of rats, new areas of binding of the preparation with proteins, including the neocortex and hippocampus, were found, which may be related to the anticonvulsant and analgesic activity of gabapentin and its derivatives. It was found that the binding site of gabapentin is α-2-δ (alpha-2-delta) subunit of potential-dependent calcium channels.

In clinically significant concentrations gabapentin does not bind to other common receptors for drugs and neurotransmitters, present in the brain, including GABA_A, GABA_at, benzodiazepine, glutamate, glycine and N-methyl-D-aspartate receptors.

Gabapentin in conditions in vitro does not interact with sodium channels, which distinguishes it from phenytoin and carbamazepine. In a number of test systems in vitro The use of gabapentin resulted in a partial decrease in the response to a glutamate agonist N-methyl-Daspartate (NMDA), but only in a concentration exceeding 100 μmol / L, which is unattainable under conditions in vivo. In conditions in vitro The use of gabapentin results in an insignificant decrease in the release of monoamine neurotransmitters.

Clinical efficacy and safety

In the clinical study of adjuvant therapy of partial seizures in children aged 3 to 12 years, there were quantitative but statistically unreliable differences in the incidence of seizures by 50% in the gabapentin group compared with the placebo group. Additional analysis of the frequency of response to therapy depending on age (when considering age as a continuous variable or in the allocation of two age subgroups: 3-5 years and 6-12 years) did not reveal a statistically significant effect of age on the effectiveness of therapy.

Pharmacokinetics:

Suction

After ingestion, the maximum concentration of gabapentin in the blood plasma is reached within 2-3 hours. The bioavailability of gabapentin tends to decrease with increasing dose of the drug. Absolute bioavailability when taking 300 mg capsules is approximately 60%. Food, including high-fat, does not have a clinically significant effect on the pharmacokinetics of gabapentin. The pharmacokinetics of gabapentin does not change with multiple administration of the drug.

Distribution

Gabapentin does not bind to blood plasma proteins, and its volume of distribution is 57.7 liters. In patients with epilepsy, the concentration of gabapentin in the cerebrospinal fluid (CSF) is approximately 20% of the minimum equilibrium concentration in the blood plasma. Gabapentin excreted in breast milk.

Biotransformation

There are no data on the metabolism of gabapentin in the human body. Gabapentin does not cause induction of nonspecific liver oxidases responsible for the metabolism of drugs.

Excretion

Gabapentin is excreted unchanged exclusively by renal excretion.The half-life of gabapentin does not depend on the dose taken and is on average 5 to 7 hours.

In elderly people and patients with impaired renal function clearance of gabapentin from plasma is reduced. The elimination constant, plasma clearance and renal clearance of gabapentin are directly proportional to the creatinine clearance.

Gabapentin is removed from the blood plasma during hemodialysis. Patients with impaired renal function or who are on hemodialysis are recommended to adjust the dose of the drug (see section "Method of administration and dose").

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 older than 5 years is similar to that of adults when using the drug in an equivalent dose based on the calculation of mg / kg of body weight.

In the study of pharmacokinetics in 24 healthy children aged 1 to 48 months, the exposure parameters of the drug (AUC) were approximately 30% lower. FROM_mOh - lower, and the clearance is higher when calculated per unit body weight in comparison with the available published data on the kinetics of the drug in children over the age of 5 years.

Linearity / non-linearity of pharmacokinetics parameters

The bioavailability of gabapentin decreases with increasing dose, which leads to a non-linearity of the pharmacokinetics parameters, which include the bioavailability index (F), for example, Ae%, CL/F, Vd/F. Pharmacokinetics of elimination (parameter parameters, not including F, such as CLr and T_1/2) better described by a linear model. Equilibrium concentrations of gabapentin in blood plasma are predictable based on kinetics data for a single dose.

Indications:

- Treatment of neuropathic pain in adults aged 18 years and older (efficacy and safety in patients under the age of 18 years are not established);

- monotherapy of partial seizures with secondary generalization and without it in adults and children aged 12 years and older (efficacy and safety of monotherapy in children under 12 years of age are not established);

- as an additional tool in the treatment of partial seizures with secondary generalization and without it in adults and children aged 3 years and older (safety and effectiveness of additional therapy with gabapentin in children less than 3 years of age have not been established).

Contraindications:

- Increased sensitivity to gabapentin or ancillary components of the drug;

- children under 18 years of age in the treatment of neuropathic pain;

- children under 12 years of age with monotherapy of partial seizures with secondary generalization and without it;

- children under 3 years of age when used as an additional agent in the treatment of partial seizures with secondary generalization and without it.

Carefully:

Renal failure (see section "Method of administration and dose").

Pregnancy and lactation:

The general risk caused by epilepsy and antiepileptic drugs

The risk of the birth of children with congenital anomalies in mothers who are treated with anticonvulsant drugs is increased by 2-3 times. Most often observed cleft of the upper lip and palate, malformations of the cardiovascular system and neural tube defects. In this case, the use of several 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, as well as all women who may have pregnancy, should consult a qualified specialist.In case a woman plans a pregnancy, one should once again assess the need for continuing anticonvulsant therapy. In this case, anticonvulsants should not be abruptly abolished, as this can lead to the resumption of seizures with severe consequences for the mother and child. In rare cases, children whose mothers have epilepsy have experienced a developmental delay. It is not possible to determine whether developmental delay is related to genetic or social factors, maternal illness or anticonvulsant therapy.

The risk caused by gabapentin

There are no data on the use of the drug in pregnant women. In animal experiments, the toxicity of the drug against the fetus was demonstrated. As for the possible risk, people do not have data. therefore gabapentin should be used during pregnancy only if the intended benefit to the mother justifies the possible risk to the fetus.

In cases where there are reports, it is impossible to say with certainty whether gabapentin is accompanied during pregnancy by an increased risk of malformations, first, due to the presence of epilepsy proper, and secondly, because of the use of other anticonvulsants .

Breast-feeding

Gabapentin is excreted in breast milk, its influence on the infant is unknown, therefore during breastfeeding gabapentin should be prescribed only if the benefit to the mother clearly outweighs the risk to the baby.

In studies on animals, gabapentin has not been shown to influence fertility.

Dosing and Administration:

Inside, regardless of food intake. If it is necessary to reduce the dose, cancel the drug or replace it with an alternative remedy, this should be done gradually for at least one week.

Neuropathic pain in adults

The initial dose is 900 mg / day in three doses in equal doses; if necessary, depending on the effect, the dose is gradually increased to a maximum of 3600 mg / day. It should be borne in mind that when additional gabapentin is administered at a dose above 1800 mg / day, no additional efficacy is noted.

Treatment can begin immediately with a dose of 900 mg / day (300 mg 3 times a day) or you can increase the dose gradually to 900 mg per day for the first 3 days according to the following scheme:

Day 1: 300 mg once a day;

Day 2: 300 mg twice a day;

3-th day: 300 mg 3 times a day.

Partial cramps

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

Adults and children over the age of 12: effective dose - from 900 to 3600 mg / day. Therapy can begin with a dose of 300 mg 3 times a day on the first day or increase gradually to 900 mg according to the scheme described above (see subsection "Neuropathic pain in adults"). Subsequently, the dose can be increased to a maximum of 3600 mg / day (divided into 3 equal receptions). A good tolerability of the drug in doses up to 4800 mg / day was noted. The maximum interval between doses with a triple take of the drug should not exceed 12 hours in order to avoid the resumption of seizures.

Children aged 3-12 years: the initial dose of the drug varies from 10 to 15 mg / kg / day, which is given in equal doses 3 times a day and increased to about 3 days. Effective dose of gabapentin in children aged 5 years and older is 25-35 mg / kg / day in equal doses of 3 doses. The effective dose of gabapentin in children aged 3 to 5 years is 40 mg / kg / day in equal doses of 3 doses. A good tolerability of the drug in doses up to 50 mg / kg / day with long-term use was noted.The maximum interval between taking doses of the drug should not exceed 12 hours in order to avoid the resumption of seizures.

There is no need to monitor the concentration of gabapentin in the blood plasma. It can be used in combination with other anticonvulsants without taking into account changes in its concentration in the blood plasma or the concentration of other anticonvulsants in the serum.

Patients in serious condition

In severe patients, for example, in case of a reduced body weight, after organ transplantation, etc., the dose should be increased more slowly, either by using smaller doses, or by making large intervals before increasing the dose.

Application in elderly patients (over the age of 65 years)

Due to the age-related decline in renal function, elderly patients may require dose adjustment (for more details see Table 1). Drowsiness, peripheral edema and asthenia in elderly patients can occur more often.

Selection of a dose for renal failure

Patients with renal insufficiency are recommended to reduce the dose of gabapentin according to Table 1:

Creatinine clearance (ml / min)	Daily dose (mg / day)^A
≥80	900-3600
50-79	600-1800
30-49	300-900
15-29	150^B-600
<15^AT	150^B-300

^A The daily dose should be given in three doses

^B Assign 300 mg every other day

^AT In patients with creatinine clearance <15 ml / min, the daily dose should be reduced in proportion to the creatinine clearance (for example, a patient with a creatinine clearance of 7.5 ml / min should receive half the dose that the patient receives 15 ml / min with creatinine clearance)

Recommendations for patients, on hemodialysis

Patients who are on hemodialysis who have not previously taken gabapentin, the drug is recommended to be prescribed in a saturating dose of 300-400 mg, and then apply it to 200-300 mg after every 4 hours of hemodialysis.

For patients with reduced renal function who undergo dialysis, the maintenance dose of gabapentin should be selected according to the recommendations in Table 1. In addition to maintenance therapy, 200-300 mg of gabapentin is recommended after every 4-hour dialysis procedure.

Side effects:

The adverse reactions observed in clinical studies with gabapentin are listed in accordance with organ and system damage and frequency of occurrence.

Frequency of occurrence is defined as follows: very often (≥1 / 10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1,000 to <1/100), rarely (from ≥1 / 10 000 to <1/1 000), very rarely (<1/10 000).If the frequency category was different in different studies, an undesirable reaction was assigned a higher category. Unwanted reactions, reported during the use of the drug after registration, are assigned a category of frequency "unknown" (the frequency can not be calculated on the basis of available data). In each section by frequency, unwanted 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 infections, otitis media.

Violations from the blood and lymphatic system: often - leukopenia; unknown - thrombocytopenia.

Immune system disorders: infrequently - allergic reactions, including hives; unknown - hypersensitivity, including systemic reactions such as fever, rashes, hepatitis, lymphadenopathy, eosinophilia and others.

Disorders from the metabolism and nutrition: often anorexia, increased appetite.

Disorders of the psyche: often - hostility, confusion, depression, anxiety, nervousness,violation of thinking, emotional lability; infrequent mental state; unknown - hallucinations.

Impaired nervous system: very often - drowsiness, dizziness, ataxia; often - convulsions, hyperkinesia. dysarthria, amnesia, tremor, insomnia, headache, impaired sensation (eg, paresthesia, hypoesthesia), impaired coordination, nystagmus, strengthening, weakening or lack of reflexes; infrequently - hypokinesia; rarely - loss of consciousness; unknown - other movement disorders (eg, choreoathetosis, dyskinesia and dystonia).

Disorders from the side of the organ of vision: often - visual impairment (such as, amblyopia, diplopia).

Hearing disorders and labyrinthine disturbances: often - vertigo; unknown - noise in the ears.

Heart Disease: infrequent - a feeling of palpitations.

Vascular disorders: often - symptoms of vasodilation or hypertension.

Disturbances from the respiratory system, chest and mediastinal organs: often - shortness of breath, bronchitis, pharyngitis, cough, rhinitis.

Disorders from the gastrointestinal tract: often - constipation, diarrhea, dryness of the oral mucosa or pharynx, dyspepsia, flatulence, nausea, vomiting, abdominal pain, dental diseases, gingivitis; unknown - pancreatitis.

Disorders from the liver and bile ducts: unknown - hepatitis, jaundice.

Disturbances from the skin and subcutaneous tissues: often - edema of the face, purpura (most often it was described as bruising that occurred during physical trauma), skin rash, acne, itching of the skin; unknown - Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia, skin rash, including eosinophilia and systemic reactions (see section "Special instructions").

Disturbances from the musculoskeletal and connective tissue: often - myalgia, arthralgia, back pain, twitching of muscles; unknown - rhabdomyolysis, myoclonus.

Disorders from the kidneys and urinary tract: unknown - incontinence, acute renal failure.

Violations of the genitals and breast: often - impotence; unknown - an increase in the volume of mammary glands, gynecomastia, sexual dysfunction (including changes in libido, ejaculation and anorgasmia).

General disorders and disorders at the site of administration: very often fatigue, fever; often - peripheral edema, gait disturbance, asthenia, pain of different localization, general malaise, flu-like syndrome; infrequently, generalized edema; unknown - withdrawal syndrome (most often the following undesirable reactions: anxiety, insomnia, nausea, pain of various localization and increased sweating), chest pain. Cases of sudden unexplained death have been reported, whose association with treatment with gabapentin has not been established.

Laboratory and instrumental data: often - reducing the concentration of white blood cells, weight gain; infrequently - increased activity of alanine aminotransferase, aspartate aminotransferase and bilirubin concentration in blood plasma, hyperglycemia; rarely - hypoglycemia (mainly in patients with diabetes mellitus); unknown - hyponatremia, increased activity of creatine phosphokinase.

Trauma, intoxication and complications of manipulation: often - injuries, fractures, abrasions associated with falls.

There are reports of the development of acute pancreatitis with gabapentin therapy. The causal relationship with gabapentin remains unclear (see Fig.section "Special instructions").

There are reports of cases of myopathy with an increase in creatine kinase activity in patients with terminal stage of renal failure who are on hemodialysis.

Cases of respiratory tract infection, otitis media, bronchitis and seizures were noted only in clinical studies. In addition, clinical studies reported cases of aggressive behavior and hyperkinesis in children.

Overdose:

With a single administration of 49 g of gabapentin, the following symptoms: dizziness, double vision, speech impairment, drowsiness, loss of consciousness, a state of inhibition, and mild diarrhea, which completely disappeared during symptomatic therapy.

It should be borne in mind that after taking high doses of gabapentin, its absorption in the intestine decreases.

With overdose of gabapentin, the development of coma is possible, especially with the simultaneous use of other drugs suppressing the central nervous system.

Although gabapentin can be inferred when hemodialysis, the experience shows that usually such a need does not arise.Patients with severe renal insufficiency can be shown hemodialysis.

Interaction:

There are reports of spontaneous cases, and according to information from literature sources, respiratory depression and / or sedation symptoms associated with taking gabapentin and opioid analgesics are possible. In some of these cases, the authors linked these symptoms with simultaneous use of gabapentin and opioids, especially in elderly patients.

When 600 mg of gabapentin was used 2 hours after the administration of morphine in the form of capsules with prolonged release of 60 mg, an increase in the mean value AUC gabapentin by 44% compared with monotherapy with gabapentin, which is associated with an increase in the pain threshold (cold pressor test). The clinical significance of this change has not been established, the pharmacokinetic characteristics of morphine remain unchanged. Undesired reactions with the joint administration of morphine and gabapentin did not differ from those when taking morphine together with placebo. The degree of interaction of these drugs in other doses is unknown.

Interactions between gabapentin and phenobarbital, phenytoin, valproic acid and carbamazepine have not been observed.The pharmacokinetics of gabapentin in the equilibrium state is the same in healthy people and patients receiving other anticonvulsants.

The simultaneous 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 bioavailability of gabapentin by approximately 24% (see section "Special instructions").

Probenecid does not affect renal excretion of gabapentin.

A slight decrease (14%) of renal excretion of gabapentin with concurrent administration of cimetidine is probably of no clinical significance.

With the simultaneous use of naproxen (250 mg) and gabapentin (125 mg), there was an increase in absorption of gabapentin from 12% to 15%. Gabapentin does not affect the pharmacokinetic parameters of naproxen. These doses of drugs are less than the minimum therapeutic dose. Simultaneous use of these drugs in large doses has not been studied.

Special instructions:

Suicidal Ideas and Behavior

Antiepileptic drugs, including gabapentin, may increase the risk of suicidal thoughts or behavior, but the mechanism of their development is unknown. A meta-analysis of randomized placebo-controlled studies of antiepileptic drugs demonstrated a slight increase in the risk of suicidal thoughts and behavior.

Therefore, patients receiving these drugs should be carefully monitored for the appearance or deterioration of depression, the appearance of suicidal thoughts or behavior, as well as for any changes in behavior. In case of signs of suicidal thoughts or behavior, patients or their caregivers should consult a doctor.

Acute pancreatitis

In the case of acute acute pancreatitis, taking gabapentin should evaluate the possibility of discontinuing the drug.

Convulsions (withdrawal syndrome)

Although the syndrome of "cancellation", accompanied by the development of seizures in the treatment of gabapentin is not checked, abrupt cessation of therapy anticonvulsants in epileptic patients may provoke the development of status epilepticus (see. Section "Dosage and administration").

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

As with other anticonvulsants, attempts to abolish all associated antiepileptic drugs in order to initiate gabapentin monotherapy in the case of refractory treatment for patients taking several anticonvulsants do not generally end in success.

It is believed that gabapentin It is ineffective in primary generalized seizures, for example, absences, and can even intensify such seizures in some patients. In this regard, apply gabapentin patients with mixed seizures, including absences, should be treated with caution.

Elderly patients

Systematic studies of patients aged 65 years and older receiving gabapentin, were not conducted. In a double-blind study of the use of gabapentin in neuropathic pain, a higher incidence of drowsiness, peripheral edema and asthenia was observed in patients aged 65 years and older compared with patients <65 years of age. With the exception of these results, a clinical examination of this group of patients showed that the side effects profile did not differ from the others.

Children

The effect of prolonged therapy (more than 36 weeks) with gabapentin on learning ability, intelligence and child development has not been sufficiently studied. It is necessary to estimate the ratio of possible risk and benefit in the appointment of long-term therapy.

Abuse and dependence

In the database of post-registration observations there are reports of cases of drug abuse and dependence. As with any drug that affects the central nervous system, doctors should carefully study the history of patients for drug abuse and monitor them to identify possible signs of abuse of gabapentin (eg, the desire to unreasonably obtain the drug, the development of resistance to gabapentin., An unreasonable increase in the dose of the drug ).

DRESS-syndrome

Against the background of taking antiepileptic drugs, including gabapentin, there have been reports of cases of development of severe life-threatening hypersensitivity reactions, such as drug rash with concomitant eosinophilia and systemic symptoms. It should be remembered that early signs of hypersensitivity reactions, such as fever, lymphadenopathy,can develop even in the absence of skin rash. In the case of such symptoms, an immediate examination of the patient is necessary. If no other cause is found other than gabapentin, the drug should be discontinued.

Laboratory Tests

With the joint use of gabapentin and other anticonvulsants, false-positive results were detected in determining the protein in the urine using test strips Ames N-Multistix SG^®. To determine the protein in the urine it is recommended to use a more specific method of precipitation with sulfosalicylic acid.

Effect on the central nervous system

During the treatment with gabapentin, there were cases of dizziness and drowsiness, which may increase the chance of accidental injury (in the fall). In the post-registration period, there were also reported cases of confusion, loss of consciousness and mental disorders. Therefore, patients should be cautioned until they know the possible effects of this medication.

With simultaneous use with opioid analgesics, there may be an increase in the concentration of gabapentin in blood plasma.In this regard, the patient needs careful observation 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 "Interaction with other drugs").

Joint use with antacids

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

Effect on the ability to drive transp. cf. and fur:

When taking the drug, patients are not advised to drive vehicles or use potentially dangerous equipment until confirmation of the absence of negative effects of the drug on the performance of these functions.

Gabapentin affects the central nervous system and can cause dizziness, drowsiness, confusion, loss of consciousness or other symptoms from the side of the central nervous system. Even with little or moderate severity, these undesirable effects can be dangerous for patients driving vehicles or other mechanisms. This probability is especially great at the beginning of treatment or after increasing the dose of gabapentin.

Form release / dosage:Capsules, 300 mg.

Packaging:

For 10 or 15 capsules in a contour mesh box made of polyvinyl chloride film and aluminum foil.

5 contour cell packs of 10 capsules or 3 contour packs of 15 capsules together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000847/10

Date of registration:10.02.2010 / 23.01.2015

Expiration Date:Unlimited

The owner of the registration certificate:PIK-PHARMA, LLC PIK-PHARMA, LLC Russia

Manufacturer: & nbsp

PIC-PHARMA PRO, LLC Russia

Representation: & nbspPIK-PHARMA LLC PIK-PHARMA LLC Russia

Information update date: & nbsp03.04.2017

Illustrated instructions

Instructions

Gabapentin (Gabapentin)