Use of Gabagamma® in the treatment of painful diabetic neuropathy

Pharmacological properties of the drug Gabagamma

Gabapentin is a cyclic structural analogue of GABA, which penetrates well through the BBB. Despite its structural similarity to GABA, gabapentin is not a GABA mimetic or GABA-α and GABA-β receptor agonist. It also does not interact with benzodiazepine, glutamate, N-methyl-D-aspartate and strychnine-insensitive glycine receptors. However, highly specific (as yet unidentified) gabapentin binding centers have been identified in the neocortex and hippocampus of the animal brain. Thus, the mechanism of the antiepileptic effect of the drug remains unclear today. Bioavailability is disproportionate to the dose: with increasing dose it decreases, and at a dose of 300 mg it is 60%, at a dose of 1600 mg - 30%, respectively. Absolute bioavailability - 60%. Foods, including those high in fat, do not affect pharmacokinetics. The time required to achieve maximum concentration is 2–4 hours. Plasma concentration is proportional to the dose. The maximum concentration is 4.02 mcg/ml when used at a dose of 300 mg every 8 hours and 5.5 mcg/ml when used at a dose of 400 mg. AUC, respectively, is 24.8 and 33.3 mcg/ml/h. Penetrates through the blood-brain barrier and enters breast milk. Distribution volume - 57.7 l. In patients with epilepsy, the concentration in the CSF is approximately 20% of the corresponding equilibrium concentrations of the drug in the blood plasma. The binding to plasma proteins is very weak (less than 5%). It is practically not metabolized, does not induce oxidative enzymes with mixed function, which take part in the metabolism of the drug. Excreted by the kidneys. Removal from blood plasma has a linear relationship. The half-life is on average 5-7 hours, does not depend on the dose (at a dose of 300 mg - 5.2 hours, 400 mg - 6.1 hours). Excreted during hemodialysis. The clearance of gabapentin from blood plasma is reduced in elderly people and in patients with impaired renal function; the half-life with a creatinine clearance of 30 ml/min is 52 hours. Pharmacokinetics do not change with repeated use.

Use of Gabagamma® in the treatment of painful diabetic neuropathy

A.B. Danilov, Moscow Medical Academy named after. THEM. Sechenov, Russia

From the point of view of pathophysiology, nociceptive and neuropathic pain are distinguished [1, 7]. Nociceptive is pain caused by the influence of any factor (mechanical trauma, burn, inflammation, etc.) on peripheral pain receptors when all parts of the nervous system are intact. Neuropathic refers to pain that occurs due to organic damage or dysfunction of various parts of the nervous system. Neuropathic pain can be caused by damage to the nervous system at any level, from peripheral nerves to the cerebral cortex. In neurology, the term "neuropathic pain" or "neuropathic pain" usually refers to a peripheral nerve disorder. In this regard, there may be a misconception that neuropathic pain occurs exclusively with peripheral neuropathy or polyneuropathy. It should be emphasized once again that the term “neuropathic pain” indicates a pain syndrome that occurs when there is damage or dysfunction of both the peripheral and central nervous systems.

In the population, neuropathic pain occurs in 1-1.5% of cases. Today it unites a whole group of chronic pain syndromes that were previously considered independently. This group includes pain syndrome in various mono- and polyneuropathies. Most often, pain occurs in diabetic and alcoholic polyneuropathies (25-45%). Postherpetic neuralgia (in old age, this complication occurs in 70% of cases of herpes zoster) is also a variant of neuropathic pain. Neuropathic forms of pain syndrome include complex regional pain syndrome (local pain with swelling, trophic disorders and osteoporosis), which was previously designated as reflex sympathetic dystrophy. Typical examples of neuropathic pain are trigeminal neuralgia, phantom pain, post-stroke central pain, pain syndrome in multiple sclerosis, syringomyelia, and spinal cord lesions. According to various authors, the frequency of neuropathic pain in diabetic polyneuropathy reaches 45%, multiple sclerosis - 28%, syringomyelia - 75%, cerebral stroke - 8%, nerve injury - 5%. Among all patients with neuropathic pain, about 50% are patients with diabetic polyneuropathy. Unfortunately, pain in these patients is often interpreted as vascular or vertebrogenic, which leads to inadequate therapeutic measures. Nociceptive pain is more often acute, and neuropathic pain is chronic. In certain cases, there is a combination of nociceptive and neuropathic components of pain (with compression radiculopathies). Neuropathic pain has some characteristics. First of all, it is accompanied by specific sensory disorders. Very characteristic of neuropathic pain is allodynia - the occurrence of pain in response to a stimulus that does not normally cause pain. In such cases, patients experience severe pain at the slightest touch, sometimes even when the wind blows. There are temperature and mechanical allodynia. Mechanical allodynia is divided into static (appears when pressure is applied to a fixed point on the skin) and dynamic (occurs when moving stimuli, for example, slight irritation of the skin with a brush or finger).

With neuropathic pain, hyperesthesia, hyperalgesia, hyperpathy, and neuralgia are often observed. With hyperalgesia, sensitivity to a painful stimulus is significantly higher than expected normally. In hyperpathy, the subjective response to both painful and non-painful stimuli is excessive and often persists for a long time after the irritation has ceased. The phenomenon of neuralgia (trigeminal, postherpetic) is a typical example of neuropathic pain. The patient may also be bothered by spontaneous pain that occurs in the apparent absence of any external influence. They usually have a burning, stabbing character. The sensation of tickling, painless tingling, or other similar sensations is referred to as paresthesia; if these sensations cause pain, they are called dysesthesia.

Pathophysiology of neuropathic pain

The pathophysiological mechanisms of neuropathic pain syndrome are complex. Neuropathic pain occurs as a result of impaired interaction between nociceptive and antinociceptive systems due to their damage or dysfunction at various levels of the nervous system. The role of peripheral nerves, roots, dorsal horn of the spinal cord, pain neurotransmitters, glutamate receptors, sodium and calcium channels has been most studied. Possible mechanisms of pain include spontaneous ectopic activity of damaged axons, sensitization of pain receptors, abnormal interactions of peripheral sensory fibers, and hypersensitivity to catecholamines. Much attention is paid to the study of the mechanisms of central sensitization, the “inflating” phenomenon, and the insufficiency of antinociceptive descending influences on the dorsal horn of the spinal cord (central disinhibition) [1, 7]. Central sensitization of a group of spinal cord neurons results from neuronal plasticity activated by primary afferent stimulation. This process is considered decisive in the formation of neuropathic pain syndrome and leads to the development of allodynia and hyperpathia. Voltage-gated calcium N channels are located in the superficial plate of the dorsal horn of the spinal cord and are involved in the formation of neuropathic pain. There is evidence of an increase in the release of neurotransmitters upon activation of N and P types of voltage-gated calcium channels. It is believed that the α2δ subunit, which is part of all voltage-gated calcium channels, is the target for the antiallodynic action of gabapentin.

Treatment of neuropathic pain

Treatment of neuropathic pain is often challenging due to the variety of treatment options. To combat it, non-drug and medicinal methods are used. Among non-drug methods, methods are used that enhance the activity of antinociceptive systems: acupuncture, transcutaneous electrical neurostimulation, spinal cord stimulation, physiotherapy, biofeedback, psychotherapy. Less commonly used are blockades and neurosurgical treatment methods (destruction of the dorsal root entry zone), which block the flow of afferent nociceptive afferentation. For pharmacotherapy of neuropathic pain, local anesthetics, opioid drugs, central muscle relaxants, antiarrhythmic drugs, antidepressants and anticonvulsants are used. It should be noted that simple analgesics (paracetamol, aspirin) and non-steroidal anti-inflammatory drugs (diclofenac, indomethacin, etc.) are ineffective for neuropathic pain and are not used for its treatment. This is due to the fact that the main mechanisms of neuropathic pain are not inflammatory processes, but neuronal and receptor disorders, peripheral and central sensitization.

Local anesthetics (lidocaine 5% cream or patch) are used to block peripheral nociceptors; Perineural injections of corticosteroids or combinations of corticosteroids and local anesthetics may be used to treat pain from mononeuropathies and neuromas. Other drugs used in patients with neuropathic pain include central muscle relaxants (baclofen, tizanidine) and opioid analgesics (morphine, codeine, oxycodone, tramadol, dextromethorphan, methodone). Certain membrane-stabilizing drugs, particularly lidocaine and mexiletine, have sometimes been prescribed for the treatment of neuropathic pain in diabetic and alcoholic polyneuropathies. However, frequent side effects limit the use of these drugs. Antidepressants are most often used for neuropathic pain, although they cause adverse reactions (especially tricyclic antidepressants) associated with anticholinergic effects, orthostatic hypotension and cardiac arrhythmias. Anticonvulsants have been used in the treatment of chronic pain since 1942 (difenin). Carbamazepine has been recognized as the drug of first choice in the treatment of trigeminal neuralgia. Information about the effectiveness of valproic acid drugs for neuropathic pain is contradictory and is mainly based on the results of uncontrolled studies and individual clinical cases. Even the earliest reports noted the limitations of anticonvulsants in the treatment of pain syndromes. Thus, their higher effectiveness was shown for pain associated with peripheral lesions compared to that for central pain. Despite the available data on the positive response of persistent pain to anticonvulsants, they still have a more pronounced effect in acute and paroxysmal pain. In addition, anticonvulsants can cause quite serious adverse reactions (anemia, hepatotoxicity, endocrinopathy, etc.). In general, antiepileptic drugs can be effective in cases where other drugs do not provide benefit or are contraindicated, so further study of new generation anticonvulsants in the treatment of pain is justified. The emergence of the new drug Gabagamma® (Verwag Pharma, Germany) has opened up new prospects in the treatment of neuropathic pain and many other chronic pain syndromes.

Use of gabapentin for neuropathic pain

Mechanism of action and properties

Gabagamma® is a structural analogue of gamma-aminobutyric acid (GABA) and is an antiepileptic drug. In animal experiments, the drug enhances the synthesis of GABA, has a modulating effect on NMDA receptors, blocks the α2δ subunit of calcium channels, reduces the release of monoamines, reduces the synthesis and transport of glutamate, and helps reduce the frequency of action potentials in peripheral nerves [7]. Probably, the combination of the above mechanisms of action ensures the high therapeutic effectiveness of gabapentin in various forms of neuropathic pain syndrome.

Gabagamma® is well tolerated and rarely causes adverse reactions (mainly mild dizziness and drowsiness). There are no signs of serious interactions between gabapentin and other drugs. However, you should refrain from using it in combination with alcohol, tranquilizers, antihistamines, barbiturates, anticonvulsants, sleeping pills, muscle relaxants, and drugs. The combination of gabapentin with lidocaine or antidepressants enhances its effect. Plasma concentrations of Gabagamma® reach their peak 2-3 hours after administration. The dosing interval should not exceed 12 hours. Bioavailability is 60%. Food intake does not affect the pharmacokinetics of gabapentin. Antacids reduce the concentration of gabapentin in the blood, so it is recommended to take it no earlier than 2 hours after taking antacids. The drug is excreted primarily by the kidneys and is not metabolized in the liver. If renal function is impaired, the dose of Gabagamma® is selected taking into account creatinine clearance. In older people, its elimination from the body slows down, so the dose should be reduced. It is known that gabapentin is excreted in breast milk, but its effect on the child’s body has not been studied. There is no information about the teratogenicity of the drug. The regimen for using gabapentin for all forms of neuropathic pain is given in Table. 2. Most often, the daily therapeutic dose of Gabagamma® is 1800-3600 mg/day.

Efficacy of gabapentin for neuropathic pain

The effectiveness of gabapentin for neuropathic pain has been studied in adequately controlled clinical trials in a sufficient number of patients.

Peripheral polyneuropathy. The effectiveness of gabapentin was confirmed in a double-blind, placebo-controlled study in 165 patients with diabetic polyneuropathy [2]. The results of other double-blind, placebo-controlled studies indicate that gabapentin is one of the most effective agents in the treatment of neuropathic pain in diabetic polyneuropathy [3, 7, 8]. The recommended dose is 1800-2400 mg/day. Treatment begins with a dose of 300 mg/day, which is increased to the recommended dose during the first week. The course of treatment is 2-4 months.

Trigeminal neuralgia. In many studies, gabapentin was effective in patients with trigeminal neuralgia that did not respond to treatment with other drugs (carbamazepine, phenytoin, valproate, amitriptyline, intravenous methylprednisolone, various nonsteroidal anti-inflammatory drugs). In most cases, complete pain relief was observed [3, 5, 15].

Complex regional pain syndrome. In a double-blind, placebo-controlled study, gabapentin caused a significant reduction in pain, improved well-being, a decrease in the severity of hyperpathia, allodynia, hyperalgesia and normalization of the color of the skin of the limb in patients with complex regional pain syndrome [14].

Lower back pain. In an open-label study, gabapentin was used for 4 weeks in 62 patients with low back pain [6]. Pain intensity decreased by an average of 46%; however, most patients were able to stop taking one or more medications they were taking before the start of the study. Gabapentin is used for back pain according to a standard regimen in the presence of a neuropathic component (compression lesions) [4].

Carpal tunnel syndrome. Gabapentin has been successfully used to treat neuropathic pain in various mononeuropathies and carpal tunnel syndromes. Its effectiveness was confirmed in a comparative study with carbamazepine in patients with carpal tunnel syndrome who were refused surgical treatment for various reasons [7].

Headache. Clinical studies have demonstrated the high effectiveness of gabapentin in the prevention and treatment of primary forms of headache [12]. In patients with migraine, treatment began with a dose of 300 mg, which was increased to 2400 mg over 2 weeks, and therapy was continued for 6 weeks. When using gabapentin, headaches occurred significantly less often, and their intensity on the visual analogue scale decreased. In addition, a decrease in the severity of accompanying symptoms was noted - nausea, photophobia, etc. The effectiveness of gabapentin was also noted in other studies in patients with migraine, accompanied and not accompanied by aura, transformed migraine, cluster headache, SUNCT syndrome [9], as well as chronic daily headache refractory to other medications [12].

Conclusion

Currently, Gabagamma® is preferred in the treatment of most forms of neuropathic pain syndrome. The advantages of the drug are the almost complete absence of contraindications, rapid onset of effect (in a week), a beneficial effect on the quality of life and minimal risk of side effects (dizziness, drowsiness).

Literature 1. Pain syndromes in neurological practice / Ed. A.M. Veina. - M., 2001. 2. Backonja M.-M. Gabapentin monotherapy for the symptomatic treatment of painful neuropathy: a multicenter, double-blind, placebo-controlled trial in patients with diabetes mellitus // Epilepsia. - 1999. - Vol. 40 (Suppl. 6). — P. 57-59. 3. Backonja M., Serra J. Pharmacologic management part 1: better-studied neuropathic pain treatments // Pain Med. - 2004. - Vol. 5 (Suppl. 1). — P. 28-47. 4. Baron R., Binder A. Is sciatica neuropathic? The mixed pain concept // Orthopade. - 2004. - Vol. 6. 5. Cheshire W. Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study // J. Pain. - 2002. - Vol. 3. - P. 137-142. 6. Hansen H. Use of gabapentin in the management of low back pain // South Med. J. - 1997. - Vol. 90. 7. Neuropathic Pain: Pathophysiology and Treatment, Progress in Pain Research and Management / Ed. by P. Hansson, H. Fields, R. Hill, P. Marchettini. - Seattle, WA: IASP Press, 2001. - P. 151-167. 8. Junker U., Brunnmuller U. Efficacy and tolerance of gabapentin in the treatment of patients with neuropathic pain. Results of an observational study involving 5620 patients // MMW Fortschr. Med. - 2003. - Vol. 145. 9. Mathew N., Rapoport A., Saper J. et al. Efficacy of gabapentin in migraine prophylaxis // Headache. - 2001. - Vol. 41. - P. 119-128. 10. Singh D., Kennedy D. The use of gabapentin for the treatment of postherpetic neuralgia // Clin. Ther. - 2003. - Vol. 25. - P. 852-889. 11. Solaro C., Ucelli A., Inglese M. et al. Gabapentin is effective in treating paroxysmal symptoms in multiple sclerosis // Neurology. - 1998. - Vol. 50 (Suppl. 4). - A147. 12. Spira P., Beran R. Gabapentin in the prophylaxis of chronic daily headache: a randomized, placebo-controlled study // Neurology. - 2003. - Vol. 61. - P. 1753-1759. 13. Stacey V., Glanzman R. Use of Gabapentin for postherpetic neuralgia: results of two randomized, placebo-controlled studies // Clin. Ther. - 2003. - Vol. 25. - P. 2597-2608. 14. Stevens R., Powar M., Stotz A. et al. Gabapentin as an analgesic in CRPS, type 1 // Reg. Anesth. Pain Med. - 1999. - Vol. 24 (Suppl.). 15. Valzania F., Strafella A., Nassetti S. et al. Gabapentin in idiopathic trigeminal neuralgia // Neurology. - 1998. - Vol. 50 (Suppl. 4). — A379.

Use of the drug Gabagamma

The dosage is determined by the doctor depending on individual tolerance and effectiveness of the drug. For individual dose selection, drugs of 100, 300, 400 mg are used. Epilepsy The effective dose is 900–3600 mg of gabapentin per day. Adults and adolescents Treatment begins with a dose of 300 mg. Increasing the dose until a clinical effect is achieved can be carried out quickly, over several days, when on the 1st day 300 mg is taken 1 time per day, on the 2nd day - 300 mg 2 times a day and on the 3rd day - 300 mg 3 once a day, in accordance with the treatment regimen:

As an alternative, an initial dose of 300 mg gabapentin (900 mg gabapentin per day) 3 times daily is possible. After this, the daily dose can be increased to 1200 mg divided into 3 single doses and, if necessary, further increased by 300 mg per day divided into 3 single doses to a maximum daily dose of 3600 mg. If a higher dose of the drug is needed and its increase occurs quickly, the risk of dizziness during the titration phase increases. The time interval between taking the evening dose and the next morning dose should be no more than 12 hours to avoid the occurrence of new epileptic seizures. Associated pain with diabetic neuropathy and postherpetic neuralgia The usual dose is 1800–2400 mg per day; in some cases it may be necessary to increase it to a maximum of 3600 mg per day. Adults Treatment begins with a dose of 100–300–400 mg. Increasing the dose until a clinical effect is achieved can be carried out quickly, over several days, when on the 1st day 100–300–400 mg is taken 1 time per day, on the 2nd day - 100–300–400 mg 2 times a day and on the 3rd day - 100–300–400 mg 3 times a day, in accordance with the treatment regimen:

After this, the dose is increased to 1800 mg per day over the course of a week, divided into 3 single doses. The following week, if necessary, the dose can be increased to 2400 mg per day, divided into 3 single doses. If necessary, it can be further increased by 300 mg per day, divided into 3 doses until the maximum dose is reached, which is 3600 mg per day. Increasing the dose to maintenance should be done slowly to prevent possible side effects. The time interval between taking the evening dose and the next morning dose should be no more than 12 hours. For patients with impaired renal function and in elderly patients, it is recommended to reduce the dose, since their renal function may be altered. Such patients need to select doses individually. Patients who are on hemodialysis The initial dose of the drug is 100–300–400 mg, followed by a maintenance dose: 200–300 mg of gabapentin after an appropriate 4-hour hemodialysis. If hemodialysis is not performed, gabapentin is not taken. For patients with unsatisfactory general condition, low body weight, or after organ transplantation, the dose of the drug should be increased gradually, prescribing 100 mg of gabapentin per capsule. Treatment for epilepsy is long-term. The doctor must independently decide in which case a forgotten dose of gabapentin (for example, the last dose taken more than 12 hours ago) should be compensated for with an additional dose that will need to be taken later. Capsules are taken orally, regardless of meals, with a sufficient amount of water, without chewing.

Gabagamma caps. 300 mg in bl. in pack No. 10x5

Name

Gabagamma

Description

100 mg capsules: white hard gelatin capsules, 300 mg capsules: yellow hard gelatin capsules, 400 mg capsules: orange hard gelatin capsules.

Main active ingredient

Gabapentin

Release form

Capsules 100 mg, 300 mg, 400 mg; 10 capsules each in blisters of PVC film and aluminum foil; 2, 5 or 10 blisters with instructions for use in a cardboard box.

Dosage

300 mg

special instructions

pharmachologic effect

Pharmacodynamics

Gabapentin readily penetrates brain tissue and prevents the development of seizures in various animal models of epilepsy. Gabapentin has no affinity for the GABA receptors (gamma-aminobutyric acid) and GABA receptors and does not affect the metabolism of GABA. Gabapentin does not bind to neurotransmitter receptors present in the brain and does not affect sodium channels. Gabapentin binds with high affinity and binds to the α-2-δ (alpha-2-delta) subunit of voltage-gated calcium channels, and gabapentin's 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 drug target molecules showed that the only target for the drug is the α-2-δ subunit. Results obtained in several preclinical models indicate that the pharmacological activity of gabapentin may be exerted by binding to the α-2-δ 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 remains to be determined. 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 α-2-δ subunit results in several distinct effects that may be responsible for its analgesic effects in animal models. The analgesic effect of gabapentin can occur 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 identified in preclinical studies is unknown.

Pharmacokinetics

After oral administration, the maximum concentration (Cmax) of gabapentin in the blood plasma is achieved within 2-3 hours. There is a tendency for gabapentin bioavailability (the portion of the drug that is absorbed) to decrease as the dose of the drug increases. The absolute bioavailability of gabapentin when taking 300 mg capsules is 60%. Food intake, including fatty foods, does not have a clinically significant effect on the pharmacokinetics of gabapentin. Repeated administration does not affect the pharmacokinetics of gabapentin. Although the plasma concentration of the drug in clinical studies varied from 2 μg/ml to 20 μg/ml, this value did not determine the effectiveness and safety of the drug. Pharmacokinetic parameters are presented in Table 1 Table 1 Summary of Mean (% CV) Pharmacokinetic parameters of gabapentin after administration of the drug every eight hours Pharmacokinetic parameters 300 mg (N = 7) 400 mg (N = 14) 800 mg (N = 14) Mean %CV Mean %CV Average %CV Cmax (MCG/ML) 4.02 (24) 5.74 (38) 8.71 (29) tmax (h) 2.7 (18) 2.1 (54) 1.6 (76) T1/2 (h) 5.2 (12) 10.8 (89) 106 (41) AUC(0-8) (µg*h/ml) 24.8 (24) 34.5 (34) 51.4 (27) Ae% (%) NA NA 47.2 (25) 34.4 (37) Cmax Maximum equilibrium plasma concentration tmax = Settling time Cmax T1/2 = Half-life AUC(0-8) = Stable area under the plasma concentration-time curve (from 0 to 8 hours after taking the drug) Ae% = percentage of the drug excreted unchanged by the kidneys from 0 to 8 hours after dosing NA = not available Distribution Gabapentin does not bind to plasma proteins. The volume of distribution of the drug is 57.7 liters. The concentration of gabapentin in the cerebrospinal fluid of patients with epilepsy is approximately 20% of the steady-state plasma concentration. Gabapentin passes into breast milk. Metabolism The metabolism of gabapentin in the human body is not completely known. The drug does not induce oxidative liver enzymes involved in drug metabolism. Excretion Gabapentin is excreted unchanged by the kidneys. The half-life of gabapentin is independent of dose and averages 5-7 hours. In adult patients and patients with impaired renal function, the plasma clearance of gabapentin is reduced. The elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. Gabapentin is eliminated from plasma by hemodialysis. In patients with impaired renal function or on hemodialysis, it is recommended to review the dose of the drug. The pharmacokinetics of gabapentin in children was assessed in 50 healthy volunteers aged 1 month to 12 years. In general, when calculating the dose per kg of body weight (mg/kg), plasma concentrations of gabapentin in children over 5 years of age are similar to those in adults.

Indications for use

Epilepsy: Gabapentin is used in adults and children 6 years of age and older as adjunctive therapy for partial-onset seizures with or without secondary generalization. Gabapentin is used in adults and adolescents 12 years of age and older as monotherapy for partial seizures with and without secondary generalization. Peripheral neuropathic pain: Gabapentin is indicated for the treatment of peripheral neuropathic pain (eg, painful diabetic neuropathy or postherpetic neuralgia) in adult patients.

Directions for use and doses

For oral use. Gabapentin can be taken with or without food; the capsule should be swallowed whole with plenty of liquid (a glass of water). When initially using the drug, regardless of the indications, dose titration is used, the scheme of which is presented in Table 1. This scheme is recommended for adults and adolescents 12 years of age and older. The dosage schedule for children under 12 years of age is presented separately. Table 1 DOSING SCHEME - INITIAL TITRATION Day 1 Day 2 Day 3 300 mg once daily 300 mg twice daily 300 mg three times daily Gabapentin Withdrawal Gabapentin should also be discontinued gradually, regardless of indication, for at least 1 week. Epilepsy Treatment for epilepsy is usually long-term. The optimal dose is determined by the doctor, depending on the effect and individual tolerance. Adults and adolescents (over 12 years of age) Effective doses for epilepsy (in clinical studies) from 900 to 3600 mg/day. Treatment begins with titration of the drug dose as described in Table 2, or with a dose of 300 mg 3 times a day on day 1. Then, depending on individual tolerability and effectiveness, the dose can be increased by 300 mg/day every 2–3 days to a maximum of 3600 mg/day. For some patients, slower titration of gabapentin may be necessary. The shortest time to achieve a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, 3600 mg is 3 weeks. In long-term open clinical studies, a dose of 4800 mg/day was well tolerated by patients. The daily dose should be divided into 3 doses. The maximum interval between doses of the drug should not exceed 12 hours to avoid interruptions in anticonvulsant therapy and prevent the occurrence of seizures. Children aged 6 years and older. The starting dose of the drug should be 10-15 mg/kg/day. An effective dose should be achieved by titrating the drug over 3 days. The effective dose of gabapentin in children 6 years of age and older is 25-35 mg/kg/day. A dose of 50 mg/kg/day has been proven to be well tolerated by patients in long-term clinical studies. The daily dose should be divided into equal parts (taken 3 times a day); the maximum interval between doses of the drug should not exceed 12 hours. There is no need to monitor gabapentin serum levels. Gabapentin can be used in combination with other antiepileptic drugs without fear of changes in plasma drug concentrations. Peripheral neuropathic pain Adults Treatment begins with dose titration as described in Table 1. Starting dose 900 mg/day. should be divided into 3 doses. Then, depending on individual tolerability and effectiveness, the dose can be increased by 300 mg/day every 2-3 days to a maximum of 3600 mg/day. For some patients, slower titration of gabapentin may be necessary. The shortest time to achieve a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, 3600 mg/day is 3 weeks. The effectiveness and safety of gabapentin in the treatment of peripheral neuropathic pain (eg, painful diabetic neuropathy or postherpetic neuralgia) have not been studied in long-term clinical studies (lasting more than 5 months). If a patient requires longer-term (more than 5 months) treatment with gabapentin for neuropathic pain, the physician should assess the patient's clinical status before continuing therapy. Use in special groups of patients Patients with severe general condition or certain aggravating factors (low body weight, post-transplant status, etc.) should be titrated more slowly, either by reducing the step dose or by lengthening the intervals between dose increases. Use in elderly patients (over 65 years of age) Elderly patients sometimes require individual dose selection due to a possible decrease in renal function (see Table 2). In older patients, the development of drowsiness, peripheral edema and asthenia is more common. Use in patients with renal failure. Patients with severe renal failure and/or patients on hemodialysis require individual dosage selection (see Table 2). For these patients, gabapentin 100 mg capsules are more often used. Table 2 GABAPENTIN DOSES FOR ADULTS, DEPENDING ON RENAL FUNCTION Creatinine clearance (ml/min) Daily dose (mg/day) of gabapentin ≥ 80 (creatinine clearance is normal) 900-3600 50-79 600-1800 30-49 300- 900 15-29 150b-600

Use during pregnancy and lactation

General risks of epilepsy and antiepileptic therapy The risk of congenital pathology in the offspring of mothers treated for epilepsy is increased by factors 2 and 3. The most commonly reported development of cleft lip, abnormalities of the heart and neural tube. Multicomponent antiepileptic therapy may be associated with a greater risk of structural abnormalities compared with monotherapy. This explains the maximum desire to use monotherapy regimens where possible. All pregnant women and women of childbearing age who require antiepileptic therapy should receive specialist advice before starting it. When planning pregnancy, it is necessary to reconsider the need for antiepileptic therapy. Abruptly stopping the use of antiepileptic drugs is unacceptable, as this can lead to seizures and significantly harm the health of the mother and child. Developmental delays in children born to mothers with epilepsy are rare. It is impossible to differentiate whether developmental delay is due to genetic disorders, social factors, maternal epilepsy, or her use of antiepileptic drugs. Risks associated with gabapentin therapy There are no adequate data on the use of gabapentin in pregnant women. Animal studies have shown the drug to be toxic to the reproductive system. The potential risk to humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the possible risk to the fetus. There is no consensus on whether gabapentin taken by women during pregnancy for epilepsy increases the risk of congenital pathology in the offspring. Gabapentin is excreted in breast milk. Since the effect of the drug on infants has not been studied, gabapentin should be prescribed to nursing women with caution. The use of gabapentin in nursing women is justified only if the benefit to the mother outweighs the potential risk to the infant.

Precautionary measures

Skin rash in combination with eosinophilia and (DRESS syndrome) Severe, life-threatening systemic hypersensitivity reactions such as DRESS syndrome (skin rash in combination with eosinophilia, fever and systemic symptoms) (see section "Side effects"). Early manifestations of hypersensitivity reactions, such as fever or lymphadenopathy, may develop when the rash is not yet apparent. If the above symptoms appear, the patient should be immediately examined by a doctor. If other causes of DRES S syndrome cannot be identified, gabapentin should be discontinued. Anaphylaxis Gabapentin may cause anaphylaxis. Signs and symptoms of reported cases have included difficulty breathing, swelling of the lips, throat and tongue, and hypotension, requiring emergency treatment. Patients should stop taking gabapentin and seek immediate medical attention if they experience signs or symptoms of anaphylaxis (see Side Effects section). Suicidal thoughts and behavior Depression and mood changes have been observed in patients treated with antiepileptic drugs. A meta-analysis of randomized placebo-controlled clinical trials of antiepileptic drugs found a nonsignificant increase in the risk of suicidal ideation and behavior. The mechanism for this increase is unknown, and available information does not exclude the possibility of an increased risk of suicide when taking antiepileptic drugs. Patients should be closely monitored for signs of depression, suicidal thoughts or behavior. If signs of depression and/or suicidal thoughts or behavior occur, patients should be advised to seek immediate medical attention from a physician. Acute pancreatitis If acute pancreatitis develops during the use of gabapentin, discontinuation of gabapentin is indicated (see section “Side Effects”). Epilepsy Although there is no evidence of resumption of seizures with gabapentin, abrupt withdrawal of anticonvulsants in patients with epilepsy may contribute to the development of status epilepticus (see section "Dosage and Administration"). As with other antiepileptic drugs, some patients may experience an increase in the frequency of seizures or new types of seizures while using gabapentin. As with other antiepileptic drugs, attempts to discontinue concomitant antiepileptic drugs to switch to gabapentin monotherapy in patients receiving multiple antiepileptic drugs are rarely successful. Gabapentin is not considered effective for the treatment of primary generalized seizures, such as absence seizures, and may increase the intensity of such seizures in some patients. For this reason, gabapentin should be used with caution in patients with mixed seizures that include absence seizures. Concomitant Use with Opioids Patients who require concomitant treatment with opioids should be closely monitored for signs of central nervous system (CNS) depression, such as somnolence, sedation, and respiratory depression. Patients using gabapentin and morphine concomitantly may experience increased gabapentin concentrations. The dose of gabapentin or opioids should be reduced appropriately. Respiratory depression Gabapentin is associated with the development of severe respiratory depression. Patients with impaired respiratory function, respiratory or neurological diseases, renal failure, concomitantly taking central nervous system suppressants, or elderly patients may be at higher risk of developing this severe adverse reaction. It may be necessary to adjust the dose of the drug in this category of patients. Elderly patients (over 65 years of age) Gabapentin has not been systematically studied in patients aged 65 years or older. In one double-blind study of patients with neuropathic pain, patients over 65 years of age were more likely than younger patients to develop drowsiness, peripheral edema, and weakness. Apart from these data, clinical studies in this age group have found no evidence of a different adverse event profile from that in a younger patient population. Use in Children and Adolescents The effects of long-term (greater than 36 weeks) use of gabapentin on learning, intelligence, and development in children and adolescents have not been adequately studied. In this regard, when deciding on the need for long-term therapy, possible risks should be taken into account. Abuse and Dependence Cases of abuse and dependence have been reported in post-marketing studies. Patients with a history of substance abuse should be carefully assessed and monitored for signs of possible gabapentin abuse, e.g. increasing the dose, developing tolerance. Laboratory Tests Semi-quantitative dipstick tests for protein in urine may result in false positives. Therefore, if necessary, it is recommended to carry out additional analyzes using other methods (biuret method, turbidimetric method, dye tests). Patients with rare hereditary diseases, for example, lactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, should not take the drug. Gabapentin may affect your ability to drive and use mechanical equipment. Gabapentin affects the central nervous system and may cause drowsiness, dizziness, or other symptoms. Thus, gabapentin, even when used as directed, can reduce reaction speed and impair the ability to drive vehicles or work in hazardous work. This is especially true at the beginning of treatment and after increasing the dose of the drug, as well as while taking alcohol.

Interaction with other drugs

Antiepileptic drugs: After the administration of gabapentin, pharmacokinetic studies showed no significant changes in the plasma concentrations of phenytoin, carbamazepine, valproic acid, or phenobarbital, which were used as basic therapy. There were also no changes in the pharmacokinetics of gabapentin. Oral contraceptives: Co-administration of gabapentin and oral contraceptives containing norethisterone and/or ethinyl estradiol does not affect the steady-state concentrations of these drugs. Antacids: Concomitant administration of gabapentin and antacids containing aluminum or magnesium reduces the bioavailability of gabapentin by 24%. It is recommended to take gabapentin no earlier than 2 hours after taking antacids. Cimetidine: When used simultaneously with cimetidine, a clinically insignificant decrease in the excretion of gabapentin by the kidneys was observed. Alcohol and other drugs that affect the central nervous system can increase the side effects of gabapentin from the central nervous system (drowsiness, ataxia, etc.). Morphine: In a study of healthy volunteers (N=12) administered morphine 60 mg controlled-release capsules 2 hours before gabapentin (600 mg capsule) there was a 44% increase in the mean AUC for gabapentin compared with cases when morphine was not used. Therefore, when morphine and gabapentin are used concomitantly, close monitoring of patients is necessary to promptly recognize symptoms of CNS depression, such as somnolence, and reduce the dose of gabapentin. The use of probenecid does not interfere with the renal excretion of gabapentin.

Contraindications

Hypersensitivity to the active component of the drug (gabapentin) or to excipients. Acute pancreatitis. Children's age up to 6 years.

Compound

1 capsule 100 mg contains: active substance: gabapentin 100 mg, excipients: anhydrous lactose, corn starch, talc, gelatin, titanium dioxide (E171). 1 capsule 300 mg contains: active substance: gabapentin 300 mg, excipients: anhydrous lactose, corn starch, talc, gelatin, titanium dioxide (E171), yellow iron oxide. 1 capsule 400 mg contains: active substance: gabapentin 400 mg, excipients: anhydrous lactose, corn starch, talc, gelatin, titanium dioxide (E171), yellow iron oxide, red iron oxide.

Overdose

Even in case of overdose up to 49 g/day. No acute life-threatening toxicity has been described. In case of overdose, dizziness, double vision, dysarthria, drowsiness, lethargy and mild diarrhea may occur. During maintenance therapy, all undesirable effects were eliminated. Decreased absorption of gabapentin at high doses may limit drug absorption and reduce toxic effects from overdose. Although gabapentin can be eliminated from the blood by hemodialysis, this is not usually required. However, in patients with severe renal failure, hemodialysis may be prescribed. It was not possible to determine the lethal dose of the drug, despite testing doses of up to 8000 mg/kg. Symptoms of acute toxicity in animals included: ataxia, difficulty breathing, ptosis, decreased activity or, conversely, increased excitability. Overdose of gabapentin, especially in combination with other drugs that depress the central nervous system, can lead to coma.

Side effect

During studies on the treatment of epilepsy (as adjunctive therapy or monotherapy) and neuropathic pain, the following adverse reactions were noted (listed according to their frequency): very common (> 1/10), common (> 1/100 - 1/1000 - 1/10,000 —

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 expiration date indicated on the package.

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Side effects of the drug Gabagamma

from the cardiovascular system: symptoms of vasodilation, increased blood pressure; from the digestive system: dyspepsia; rarely - nausea, vomiting, abdominal pain, increased appetite; in isolated cases - dry mouth, constipation or diarrhea, pancreatitis, increased activity of liver transaminases, flatulence, anorexia, gingivitis. from the musculoskeletal system: rarely - myalgia, arthralgia, back pain; from the nervous system: drowsiness, dizziness, ataxia, nystagmus (dose-dependent), tremor, dysarthria, increased nervous excitability; rarely - headache, amnesia, depression; in isolated cases - thinking disorders, confusion, tic, paresthesia (dose-dependent), asthenia, hyperkinesia; hypo- or areflexia, anxiety, insomnia; from the respiratory system: rarely - rhinitis, pharyngitis, cough, pneumonia; from the genitourinary system: in isolated cases - urinary incontinence, decreased potency, urinary tract infections; from the senses: visual impairment (diplopia, amblyopia), ringing in the ears; from the hematopoietic organs: in isolated cases - leukopenia, thrombocytopenic purpura; allergic reactions: in isolated cases - skin rashes, itching, chills, exudative erythema multiforme (including Stevens-Johnson syndrome); others: weight gain, in isolated cases - peripheral edema, discoloration of tooth enamel, acne, facial swelling, changes in blood glucose levels in patients with diabetes, increased bone fragility.

Special instructions for the use of the drug Gabagamma

Reducing the dose, discontinuing the drug or replacing it with another (alternative) should be carried out gradually, over a period of at least 1 week. Abrupt cessation of treatment with antiepileptic drugs in patients with epilepsy can provoke status epilepticus. Caution should be exercised when treating patients with a history of psychosomatic illnesses. Patients with rare hereditary galactose intolerance, lactose deficiency or glucose and galactose malabsorption should not take this medicinal product. The use of alcohol and drugs may increase the side effects of gabapentin on the central nervous system, such as obnibulation of consciousness and ataxia. The use of the drug during pregnancy and lactation is possible only when the expected benefit to the mother's body outweighs the potential risk to the fetus or child. When using the drug, you should refrain from driving vehicles and working with potentially dangerous mechanisms. Gabapentin is not recommended for the treatment of epilepsy in children under 12 years of age, as well as for the treatment of diabetic neuropathy and postherpetic neuralgia in adolescents under 18 years of age, which are accompanied by pain, since experience with the drug in these groups is limited.

Gabagamma®

Suicide, suicidal ideation, or clinical deterioration

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) were not observed during treatment with gabapentin; it is not recommended to abruptly stop treatment. Cancellation of any anticonvulsants in patients with epilepsy can provoke status epilepticus. Also, as in the case of other anticonvulsants, attempts to cancel all concomitant antiepileptic drugs, begin monotherapy with gabapentin In cases of refractory treatment, 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 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 them 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 precipitation method of sulfosalicylic acid.

Effect on the central nervous system

During treatment with gabapentin, cases of dizziness and drowsiness have been observed, which may increase the likelihood of accidental injury (from a fall). Cases of confusion, loss of consciousness and mental impairment have also been reported during the post-marketing period. Therefore, patients should 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. In this regard, the patient needs to be closely monitored for the development of signs of CNS depression, such as drowsiness, sedation, and respiratory depression. Doses of gabapentin or opioid analgesics should be reduced accordingly.

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.

Drug interactions Gabagamma

Possible simultaneous use with other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital), with oral contraceptives (containing norethindrone and/or ethinyl estradiol), with drugs that block tubular secretion and reduce the excretion of gabapentin by the kidneys. Antacids that contain Al3+ and Mg2+ reduce the bioavailability of gabapentin by approximately 20%. Gabapentin is recommended to be taken 2 hours after taking the antacid drug. Myelotoxic drugs - increased hematotoxicity (leukopenia).