Neurontin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT N'UROPENTINE® (NUROPENTINE®)

Composition:

Active substance: gabapentin;

1 hard capsule contains 300 mg of gabapentin;

Excipients: mannite (E 421), maize starch, magnesium stearate, talc, colloidal anhydrous silicon dioxide; hard gelatin capsule: gelatin, purified water, iron oxide red (E 172), titanium dioxide (E 171).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules of size 1 with a white body and red cap, containing a white or almost white powder.

Pharmacotherapeutic group.
Antiepileptic agents. ATC code N03AX12.

Pharmacological Properties

Pharmacodynamics

Gabapentin, 1-(aminomethyl)cyclohexaneacetic acid, is a cyclic analogue of gamma-aminobutyric acid (GABA) capable of crossing the blood-brain barrier. The anticonvulsant activity of gabapentin has been demonstrated in numerous experimental seizure models. The mechanism of gabapentin's antiepileptic action is currently unknown. Despite structural similarity to GABA, gabapentin is not a GABA mimetic, as it does not bind to either GABA_A or GABA_B receptors, does not inhibit GABA reuptake, and does not affect GABA degradation via GABA transaminase. It does not interact with voltage-dependent sodium channels, benzodiazepine receptors, excitatory neurotransmitter binding sites, or influence catecholaminergic, acetylcholinergic, or opioid receptors. Thus, gabapentin has a completely novel mechanism of action, binding to highly specific sites in the central nervous system (CNS) of protein nature, predominantly localized in the neocortex, and having no affinity for other antiepileptic agents.

Gabapentin is also effective in suppressing neuropathic pain.

Pharmacokinetics

Absorption is rapid. Bioavailability is approximately 60%. Bioavailability is not proportional to dose: as the dose increases, bioavailability decreases, being 60% at a dose of 300 mg and 30% at a dose of 1600 mg. Food does not affect the pharmacokinetics of gabapentin. Time to reach maximum plasma concentration is 2–3 hours. Plasma concentration of the drug is proportional to the dose. Pharmacokinetics do not change with repeated administration. Gabapentin crosses the blood-brain barrier: in patients with epilepsy, the concentration of gabapentin in cerebrospinal fluid is approximately 20% of the corresponding steady-state plasma concentration. It passes into breast milk. Gabapentin does not bind to plasma proteins; the volume of distribution is 57.7 liters. Gabapentin is virtually not metabolized. It does not induce hepatic oxidative enzymes. It is excreted unchanged by the kidneys. Elimination half-life is independent of dose and averages 5–7 hours in patients with normal renal excretory function. In elderly patients and in patients with impaired renal function, elimination rate decreases in direct proportion to creatinine clearance levels. Gabapentin is removed from the blood during hemodialysis. Dose adjustment is recommended for patients with impaired renal function and for patients undergoing hemodialysis.

Pharmacokinetics of gabapentin in children were evaluated in 50 healthy subjects aged from 1 month to 12 years. Overall, when dosing was calculated per kilogram of body weight (mg/kg), plasma concentrations of gabapentin in children aged 5 years and older did not differ from those in adults.

Clinical characteristics.

Indications.

Epilepsy.

Gabapentin is used as an adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 6 years and older.

Gabapentin is used as monotherapy in partial seizures with or without secondary generalization in adults and children aged 12 years and older.

Neuropathic pain.

Gabapentin is indicated for the treatment of peripheral neuropathic pain, e.g., painful diabetic neuropathy and postherpetic neuralgia, in adults.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Central nervous system (CNS) depressants (including opioids)

Data from various sources (spontaneous reports and literature) indicate cases of respiratory depression, sedation, and death with concomitant use of gabapentin and CNS depressants, including opioids. These complications were predominantly observed when gabapentin was used concomitantly with opioids in debilitated patients, elderly patients, patients with serious underlying respiratory disorders, those taking multiple medications (polypharmacy), or those with substance abuse.

Morphine

In clinical studies, concomitant administration of gabapentin and morphine resulted in a 44% increase in gabapentin AUC. Therefore, patients receiving these drugs should be closely monitored for signs of CNS depression, such as somnolence, sedative effects, and respiratory depression. If such signs occur, the dose of gabapentin or morphine should be appropriately reduced.

Antiepileptic drugs (phenobarbital, phenytoin, valproic acid, carbamazepine)

No interactions between these drugs and gabapentin have been observed.

The pharmacokinetics of steady-state plasma gabapentin concentrations are similar in healthy volunteers and in patients with epilepsy receiving these antiepileptic agents.

Oral contraceptives containing norethindrone and/or ethinylestradiol
Concomitant administration with gabapentin does not affect the pharmacokinetics of these agents.

Antacids containing aluminum and magnesium

Concomitant administration of these agents with gabapentin reduces gabapentin bioavailability by 24%. Gabapentin should be taken no earlier than 2 hours after antacid administration.

Probenecid does not affect renal excretion of gabapentin.

Cimetidine

Concomitant administration of cimetidine with gabapentin results in a minor reduction in renal excretion of gabapentin, which is not clinically significant.

Special precautions for use

Severe skin adverse reactions (SSARs)

Severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported with gabapentin use. Patients should be informed about the signs and symptoms of these reactions, and skin reactions should be closely monitored. If signs or symptoms suggestive of these reactions occur, gabapentin should be discontinued immediately, and alternative therapy considered (if necessary).

If a patient has developed a serious reaction such as SJS, TEN, or DRESS syndrome while taking gabapentin, treatment with gabapentin must never be resumed.

Anaphylaxis

Gabapentin may cause anaphylaxis. Cases of anaphylaxis have been reported, presenting with respiratory distress, swelling (of lips, throat, and tongue), hypotension, and requiring emergency intervention. Patients should be advised to discontinue gabapentin and seek immediate medical attention if any signs of anaphylaxis occur.

Suicidal thoughts and behavior

Suicidal thoughts and behavior have been observed in patients treated with antiepileptic drugs for various indications. A meta-analysis of results from randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior, the mechanism of which is unknown. In the post-marketing period, cases of suicidal thoughts/behavior have been reported in patients receiving gabapentin (see section "Adverse reactions").

Patients (and caregivers) should be advised to seek medical help if signs of suicidal thoughts or behavior occur. Patients receiving gabapentin should be monitored for the emergence of suicidal thoughts and behavior, and appropriate treatment provided as needed. Consideration should be given to discontinuing gabapentin therapy if suicidal thoughts or behavior occur.

Acute pancreatitis

Gabapentin should be discontinued if symptoms suggestive of pancreatitis occur during treatment.

Seizures

Although there is no evidence of seizure recurrence after discontinuation of gabapentin, abrupt withdrawal of antiepileptic drugs in patients with epilepsy may precipitate status epilepticus (see section "Dosage and administration").

As with other antiepileptic drugs, in some patients, the frequency of seizures may increase or new types of seizures may occur during treatment with gabapentin.

Attempts to discontinue concomitant antiepileptic drugs to switch to gabapentin monotherapy in patients previously receiving multiple antiepileptic agents have rarely been successful.

Gabapentin is not considered effective in treating primary generalized seizures such as absence seizures, and may exacerbate these seizures in some patients. For this reason, gabapentin should be used with caution in patients with mixed seizure types that include absence seizures.

Gabapentin treatment has been associated with dizziness and somnolence, which may potentially increase the risk of accidental injuries (falls). Loss of consciousness, confusion, and development of psychiatric disorders have also been reported. Therefore, patients should be advised to exercise caution until their individual response to gabapentin is known.

Concomitant use with opioids and other CNS depressants

Patients receiving gabapentin concomitantly with CNS depressants, including opioids, should be closely monitored for signs of CNS depression such as somnolence, sedation, and respiratory depression. Concomitant use of morphine and gabapentin may increase gabapentin concentrations. The dose of gabapentin or CNS depressants, including opioids, should be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Gabapentin should be prescribed with caution when used concomitantly with opioids due to the risk of CNS depression. In a population-based observational case-control study in patients taking opioids, concomitant use with gabapentin was associated with an increased risk of opioid-related death compared to opioid use alone (adjusted odds ratio (aOR) 1.49 [95% CI, 1.18–1.88, p<0.001]).

Respiratory depression

Gabapentin treatment has been associated with severe respiratory depression. Patients with respiratory or neurological disorders, renal impairment, concomitant use of CNS depressants, and elderly patients are at increased risk of this serious adverse reaction. Dose adjustment may be required in such patients.

Elderly patients (over 65 years of age)

Systematic studies of gabapentin use in patients aged 65 years and older have not been conducted. In one double-blind study involving patients with neuropathic pain, somnolence, peripheral edema, and weakness occurred more frequently in patients over 65 years of age compared to younger patients. Except for these findings, clinical studies in this age group have not revealed evidence of differences in the adverse event profile compared to younger patients.

Children

Due to lack of data on the long-term (beyond 36 weeks) impact of gabapentin therapy on learning ability, intellectual capacity, and development in children, the benefits of long-term therapy should be weighed against its potential risks.

Misuse, abuse, and dependence

Gabapentin may cause drug dependence, which may occur even at therapeutic doses. Cases of abuse have been reported. Patients with a history of substance abuse may be at increased risk of misuse, abuse, and dependence on gabapentin and should therefore be treated with caution. The risk of misuse, abuse, or dependence should be carefully assessed before prescribing gabapentin.

Patients receiving gabapentin should be monitored for symptoms of misuse, abuse, or dependence, such as development of tolerance, dose escalation, and drug-seeking behavior.

Withdrawal symptoms

Withdrawal symptoms have been observed after discontinuation of both short- and long-term gabapentin treatment. Withdrawal symptoms may occur shortly after stopping treatment, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, increased sweating, tremor, headache, depression, unusual feelings, dizziness, and malaise. The potential occurrence of withdrawal symptoms after discontinuation of gabapentin may indicate drug dependence (see section "Adverse reactions"). Patients should be informed of this at the start of treatment. If discontinuation of gabapentin is required, it is recommended to do so gradually over at least one week, regardless of indication (see section "Dosage and administration").

Laboratory tests

False-positive results for urinary total protein may occur when using semi-quantitative methods such as dipstick tests. Therefore, positive results from such tests should be confirmed using methods based on different analytical principles, such as the biuret test, turbidimetric method, or dye-binding method, or these alternative methods should be used initially.

Use during pregnancy or breastfeeding

Pregnancy

General risks of epilepsy and antiepileptic drug (AED) use

Women of childbearing potential, especially those planning pregnancy, and pregnant women should be counseled regarding the potential risks to the fetus from both seizures and antiepileptic drug therapy. The need for antiepileptic therapy should be re-evaluated before pregnancy. Abrupt discontinuation of antiepileptic drugs in women being treated for epilepsy is not recommended, as this may lead to seizure occurrence and significantly worsen the condition of both mother and child. Monotherapy should be preferred when possible, as polytherapy with AEDs may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the AEDs used.

Risks associated with gabapentin therapy

Gabapentin crosses the human placenta.

Data from a Scandinavian observational study involving over 1,700 pregnant women exposed to gabapentin during the first trimester showed no increased risk of major congenital malformations in infants exposed to gabapentin in utero compared to unexposed infants, or compared to infants exposed to pregabalin, lamotrigine and pregabalin, or lamotrigine alone. Similarly, no increased risk of nervous system disorders was observed in children exposed to gabapentin in utero.

Limited evidence suggests a higher risk of low birth weight, preterm birth, but not stillbirth, intrauterine growth restriction, low Apgar score at 5 minutes, and microcephaly in infants exposed to gabapentin in utero.

Animal studies have shown reproductive toxicity.

Gabapentin may be used during the first trimester of pregnancy if clinically necessary.

Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentin in utero.

Concomitant use of gabapentin and opioids during pregnancy may increase the risk of neonatal withdrawal syndrome. Newborns should be closely monitored.

Breastfeeding period

Gabapentin passes into breast milk. As the effect of the drug on breastfed infants has not been studied, gabapentin should be used with caution in breastfeeding women. Gabapentin use in breastfeeding women is justified only if the benefit to the mother outweighs the potential risk to the infant.

Fertility

No effects on fertility were observed in animal studies.

Ability to influence reaction speed when driving or operating machinery

Gabapentin may have a minor or moderate influence on the ability to drive or operate machinery. Gabapentin acts on the CNS and may cause somnolence, dizziness, or other similar symptoms. These adverse effects, even if mild or moderate, may be potentially hazardous for patients when driving vehicles or operating other machinery, particularly at the beginning of therapy and after dose escalation.

Dosage and Administration

The medicinal product is intended for oral administration.

Gabapentin may be taken with or without food. The capsule should be swallowed whole and taken with sufficient fluid (e.g., a glass of water).

For all indications, treatment should be initiated according to the dose titration schedule presented in Table 1. This titration schedule is recommended for adults and children aged 12 years and older. The dose titration schedule for children aged 6 to 12 years is described below in a separate section.

Discontinuation of gabapentin

Gabapentin should be discontinued gradually over a minimum of 1 week, regardless of the indication.

Epilepsy

Long-term therapy is usually required for epilepsy. The dose is determined by the physician according to individual tolerability and efficacy.

Adults and children aged 12 years and older

Effective doses for epilepsy range from 900 to 3600 mg/day. Treatment should be initiated with dose titration as described in Table 1, or with a starting dose of 300 mg three times daily on Day 1. The dose may then be increased by 300 mg/day every 2–3 days, depending on individual tolerability and efficacy, up to a maximum dose of 3600 mg/day. Some patients may require slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

In long-term open-label clinical studies, a dose of 4800 mg/day was well tolerated by patients. The daily dose should be divided into three administrations. The maximum interval between doses should not exceed 12 hours to avoid interruptions in anticonvulsant therapy and prevent seizure occurrence.

Children aged 6 to 12 years

The initial dose should be 10–15 mg/kg/day. The effective dose should be achieved by titrating the drug over approximately 3 days. The effective dose of gabapentin in children aged 6 years and older is 25–35 mg/kg/day. A dose of 50 mg/kg/day was well tolerated by patients in long-term clinical studies. The total daily dose should be divided into equal parts (administered three times daily); the maximum interval between doses should not exceed 12 hours.

Monitoring serum gabapentin levels is not necessary. Additionally, gabapentin can be used in combination with other antiepileptic drugs, as it does not alter the plasma concentration of gabapentin or the serum concentrations of other antiepileptic drugs.

Peripheral neuropathic pain

Adults

Treatment should be initiated with dose titration as described in Table 1, or otherwise with a starting dose of 900 mg/day divided into three doses. The dose may then be increased by 300 mg/day every 2–3 days, depending on individual tolerability and efficacy, up to a maximum of 3600 mg/day. Some patients may require slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

The efficacy and safety of gabapentin in the treatment of peripheral neuropathic pain (e.g., painful diabetic neuropathy or postherpetic neuralgia) have not been studied in long-term clinical trials lasting more than 5 months. If a patient requires longer-term treatment (>5 months) with gabapentin for neuropathic pain, the physician should evaluate the patient's clinical status and determine the need for continued therapy.

Recommendations regarding the use of gabapentin for all indications

Patients with poor general health or certain complicating factors, such as low body weight or post-transplant status, may require slower titration, reduced stepwise dose increments, or longer intervals between dose increases.

Use in elderly patients (aged 65 years and older)

Elderly patients may sometimes require individual dose adjustment due to potentially reduced renal function (see Table 2). In elderly patients, somnolence, peripheral edema, and weakness occur more frequently.

Use in patients with renal impairment

Patients with severe renal impairment and those on hemodialysis require individual dose adjustment (see Table 2).

Dosing recommendations in renal impairment Table 2

* The total daily dose should be divided into 3 doses. Reduced doses should be used in patients with renal impairment (creatinine clearance <79 mL/min).

** Administer at a dose of 300 mg every other day.

*** For patients with creatinine clearance <15 mL/min, the daily dose should be reduced according to creatinine clearance (e.g., patients with creatinine clearance of 7.5 mL/min should receive half of the daily dose recommended for patients with creatinine clearance of 15 mL/min).

Dosing for patients undergoing hemodialysis.

For anuric patients undergoing hemodialysis who have never previously received gabapentin, the recommended loading dose is 300–400 mg*, followed by 200–300 mg* of gabapentin after every 4 hours of hemodialysis. Gabapentin should not be administered on days without hemodialysis.

The maintenance dose of gabapentin for patients on hemodialysis should be determined according to Table 2.

In addition to the maintenance dose, patients on hemodialysis are recommended to take 200–300 mg* of the drug after every 4 hours of hemodialysis.

* Administer gabapentin formulations at appropriate dosage strengths.

Children.

Gabapentin is indicated for the treatment of epilepsy in children: as adjunctive therapy in children aged 6 years and older, and as monotherapy in children aged 12 years and older.

Overdose.

Even with intake of up to 49 g/day, no acute life-threatening toxic reactions have been reported.

Symptoms of overdose included dizziness, double vision, slurred speech, somnolence, loss of consciousness, lethargy, and mild diarrhea. All patients fully recovered with supportive treatment. Reduced absorption of gabapentin at high doses may limit systemic absorption and reduce toxicity effects from overdose. Overdose of gabapentin, especially in combination with other CNS depressants, may result in coma.

Treatment is symptomatic. Although gabapentin can be removed by hemodialysis, this is generally not necessary. However, hemodialysis may be indicated in patients with severe renal impairment.

In studies in mice and rats, the lethal dose of gabapentin could not be determined, even with doses up to 8000 mg/kg. Symptoms of acute toxicity in animals included ataxia, labored breathing, ptosis, decreased activity, or conversely, increased excitability.

Adverse Reactions

During epilepsy studies (adjunctive therapy or monotherapy) and neuropathic pain studies, the adverse reactions listed below were observed (listed according to their frequency): very common (> 1/10), common (> 1/100 to <1/10), uncommon (> 1/1,000 to <1/100), and rare (> 1/10,000 to <1/1,000). If the frequency of adverse reactions varied across different studies, the highest frequency observed was included in the report.

Additional adverse reactions identified from post-marketing surveillance are included in the category "frequency not known" (cannot be estimated based on available data).

Within each frequency group, adverse effects are listed in decreasing order of severity.

Infections and infestations

Very common: Viral infection.

Common: Pneumonia; respiratory tract infection¹; urinary tract infection; infection, otitis media.

Blood and lymphatic system disorders

Common: Leukopenia.

Frequency not known: Thrombocytopenia.

Immune system disorders

Uncommon: Allergic reactions (e.g., urticaria).

Frequency not known: Hypersensitivity syndrome with cutaneous and systemic manifestations, which may include symptoms such as fever, rash, hepatitis, lymphadenopathy, eosinophilia, etc. (DRESS syndrome); anaphylaxis (see section "Special precautions").

Metabolism and nutrition disorders

Common: Anorexia, increased appetite.

Uncommon: Hyperglycemia (most frequently observed in patients with diabetes mellitus).

Rare: Hypoglycemia (most frequently observed in patients with diabetes mellitus).

Frequency not known: Hyponatremia.

Psychiatric disorders

Common: Hostility, confusion, emotional lability, depression, anxiety, nervousness, thinking abnormalities.

Uncommon: Agitation.

Frequency not known: Suicidal thoughts/behaviour, hallucinations, drug dependence.

Nervous system disorders

Very common: Somnolence, dizziness, ataxia.

Common: Seizures¹, hyperkinesia¹, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances (paraesthesia, hypaesthesia), coordination disturbances, nystagmus, increased, decreased or absent reflexes.

Uncommon: Hypokinesia, thinking abnormalities.

Rare: Loss of consciousness.

Frequency not known: Other movement disorders (including choreoathetosis, dyskinesia, dystonia).

Eye disorders

Common: Visual disturbances, e.g., amblyopia or diplopia.

Ear and labyrinth disorders

Common: Vertigo.

Frequency not known: Tinnitus.

Cardiac disorders

Uncommon: Palpitations.

Vascular disorders

Common: Increased blood pressure, vasodilation.

Respiratory, thoracic and mediastinal disorders

Common: Dyspnea, bronchitis, pharyngitis, cough, rhinitis.

Rare: Respiratory depression.

Gastrointestinal disorders

Common: Vomiting, nausea, dental condition changes, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence.

Uncommon: Dysphagia (difficulty swallowing).

Frequency not known: Pancreatitis².

Hepatobiliary disorders

Frequency not known: Hepatitis, jaundice.

Skin and subcutaneous tissue disorders

Common: Facial edema, purpura (most often described as bruises following trauma), rash, pruritus, acne.

Frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, eosinophilia with systemic symptoms (see section "Special precautions"), erythema multiforme, angioneurotic edema, alopecia.

Musculoskeletal and connective tissue disorders

Common: Arthralgia, myalgia, back pain, muscle spasms.

Frequency not known: Rhabdomyolysis, myoclonic seizures.

Renal and urinary disorders

Frequency not known: Acute renal failure, urinary incontinence.

Reproductive system and breast disorders

Common: Impotence.

Frequency not known: Breast enlargement, gynecomastia, sexual dysfunction (including libido changes, ejaculation disorders, anorgasmia).

General disorders and administration site conditions

Very common: Fatigue, fever.

Common: Peripheral edema, gait disturbance, weakness, pain, discomfort, influenza-like syndrome.

Uncommon: Generalized edema.

Frequency not known: Withdrawal reactions³, chest pain. Cases of sudden death have been reported, although a clear causal relationship with gabapentin use has not been established.

Investigations

Common: Decreased white blood cell count, weight gain.

Uncommon: Increased liver function tests (AST, ALT) and bilirubin levels.

Frequency not known: Increased creatine kinase levels⁴.

Injury, poisoning and procedural complications

Common: Accidental injury, fractures, lacerations.

Uncommon: Falls.

¹ Cases of respiratory tract infections, otitis media, seizures, and bronchitis were reported only in clinical trials involving children. Additionally, aggressive behavior and hyperkinesia were frequently observed in pediatric studies.

² Cases of acute pancreatitis have been reported during gabapentin treatment. A causal relationship with gabapentin has not been established (see section "Special precautions").

³ Withdrawal symptoms have been observed following discontinuation of both short- and long-term gabapentin therapy. Withdrawal symptoms may appear shortly after stopping treatment, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, increased sweating, tremor, headache, depression, unusual feelings, dizziness, and malaise (see section "Special precautions"). The occurrence of withdrawal symptoms after discontinuation of gabapentin may indicate drug dependence (see section "Adverse Reactions"). Patients should be informed of this at the beginning of treatment. If discontinuation of gabapentin is necessary, it is recommended to taper the dose gradually over at least one week, regardless of the indication (see section "Dosage and administration").

⁴ Cases of myopathy with elevated creatine kinase levels have been reported in patients with end-stage renal disease undergoing hemodialysis.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 capsules in a blister. 1, 3, or 10 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's address and location of operations.

54 Davydovskoho Hryhoriia Street, Sumy, Sumy Oblast, 40020, Ukraine.

INSTRUCTION

for medical use of the medicinal product

NEUROPENTIN®

(NUROPENTINE®)

Composition:

Active substance: gabapentin;

1 hard capsule contains 300 mg of gabapentin;

Excipients: mannitol (E 421), corn starch, magnesium stearate, talc, colloidal anhydrous silicon dioxide; hard gelatin capsule: gelatin, purified water, iron oxide red (E 172), titanium dioxide (E 171).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: size 1 hard gelatin capsules with white body and red cap, containing a white or almost white powder.

Pharmacotherapeutic group.

Antiepileptic drugs. ATC code N03A X12.

Pharmacological Properties

Pharmacodynamics

Gabapentin, 1-(aminomethyl)cyclohexaneacetic acid, is a cyclic analogue of gamma-aminobutyric acid (GABA) capable of crossing the blood-brain barrier. The anticonvulsant activity of gabapentin has been demonstrated in numerous experimental seizure models. The mechanism of gabapentin’s antiepileptic action is currently unknown. Despite structural similarity to GABA, gabapentin is not a GABA mimetic, as it does not bind to either GABA_A or GABA_B receptors, nor does it inhibit GABA reuptake or degradation by GABA-transaminase. It does not interact with voltage-dependent sodium channels, benzodiazepine receptors, excitatory neurotransmitter binding sites, or affect catecholaminergic, acetylcholinergic, or opioid receptors. Thus, gabapentin has a completely novel mechanism of action, binding to highly specific sites within the central nervous system (CNS) that are protein in nature and predominantly localized in the neocortex, and which have no affinity for other antiepileptic agents.

Gabapentin is also effective in suppressing neuropathic pain.

Pharmacokinetics

Absorption is rapid. Bioavailability is approximately 60%. Bioavailability is not proportional to dose: as the dose increases, bioavailability decreases, being 60% at a dose of 300 mg and 30% at a dose of 1600 mg. Food does not affect the pharmacokinetics of gabapentin. Time to maximum concentration is 2–3 hours. Plasma concentration of the drug is dose-proportional. Pharmacokinetics do not change with repeated administration. Gabapentin crosses the blood-brain barrier: in patients with epilepsy, the concentration of gabapentin in cerebrospinal fluid is approximately 20% of the corresponding steady-state plasma concentration. It is excreted into breast milk. Gabapentin does not bind to plasma proteins; the volume of distribution is 57.7 liters. Gabapentin is virtually not metabolized. It does not induce hepatic oxidative enzymes. It is excreted unchanged by the kidneys. Elimination half-life is independent of dose and averages 5–7 hours in patients with normal renal excretory function. In elderly patients and in patients with impaired renal function, elimination rate decreases in direct proportion to creatinine clearance. Gabapentin is removed from the blood during hemodialysis. Dose adjustment is recommended for patients with impaired renal function and for patients undergoing hemodialysis.

Pharmacokinetics of gabapentin in children were evaluated in 50 healthy subjects aged from 1 month to 12 years. Overall, when dosing is calculated per kilogram of body weight (mg/kg), plasma concentrations of gabapentin in children aged 5 years and older do not differ from those in adults.

Clinical characteristics.

Indications.

Epilepsy.

Gabapentin is used as an adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 6 years and older.

Gabapentin is indicated as monotherapy for partial seizures with or without secondary generalization in adults and children aged 12 years and older.

Neuropathic pain.

Gabapentin is indicated for the treatment of peripheral neuropathic pain, such as painful diabetic neuropathy and postherpetic neuralgia, in adults.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Central nervous system (CNS) depressants (including opioids)

Data from various sources (spontaneous reports and literature) indicate cases of respiratory depression, sedation, and death with concomitant use of gabapentin and CNS depressants, including opioids. These complications have been primarily observed when gabapentin was used concomitantly with opioids in patients who were debilitated, elderly, had significant underlying respiratory conditions, were on multiple medications (polypharmacy), or had a history of substance abuse.

Morphine

In clinical studies, concomitant administration of gabapentin and morphine resulted in a 44% increase in gabapentin AUC. Therefore, patients receiving these drugs should be closely monitored for signs of CNS depression, including somnolence, sedative effects, and respiratory depression. If such signs occur, the dose of gabapentin or morphine should be appropriately reduced.

Antiepileptic drugs (phenobarbital, phenytoin, valproic acid, carbamazepine)

No interactions between these drugs and gabapentin have been observed.

The pharmacokinetics of steady-state plasma concentrations of gabapentin are similar in healthy volunteers and in patients with epilepsy receiving these antiepileptic agents.

Oral contraceptives containing norethindrone and/or ethinylestradiol
Concomitant administration with gabapentin does not affect the pharmacokinetics of these agents.

Antacid medicinal products containing aluminium and magnesium
Concomitant administration of these products with gabapentin results in a 24% reduction in gabapentin bioavailability. Gabapentin should be taken no sooner than 2 hours after antacid administration.

Probenecid does not affect renal excretion of gabapentin.

Cimetidine
Concomitant administration of this drug with gabapentin results in a slight reduction in renal excretion of gabapentin, which is not clinically significant.

Special precautions for use

Severe skin adverse reactions (SSARs)

Severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported with gabapentin therapy. Patients should be informed of the signs and symptoms of these reactions, and skin reactions should be closely monitored during treatment. If signs or symptoms suggestive of these reactions occur, gabapentin should be discontinued immediately, and alternative therapy should be considered (if necessary).

If a patient develops a serious reaction such as SJS, TEN, or DRESS syndrome while taking gabapentin, re-administration of gabapentin must never be attempted.

Anaphylaxis

Gabapentin may cause anaphylaxis. Cases of anaphylaxis have been described with symptoms including respiratory distress, swelling (of lips, throat, and tongue), hypotension, and requiring emergency intervention. Patients should be warned that if any signs of anaphylaxis occur, gabapentin must be discontinued immediately and medical help sought without delay.

Suicidal thoughts and behavior

Suicidal thoughts and behavior have been observed in patients treated with antiepileptic drugs for various indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior, the mechanism of which is unknown. In the post-marketing period, cases of suicidal thoughts/behavior have been reported in patients receiving gabapentin (see section "Adverse reactions").

Patients (and caregivers) should be advised to seek medical help if signs of suicidal thoughts or behavior occur. Patients taking gabapentin should be monitored for the emergence of suicidal thoughts and behavior, and appropriate treatment should be initiated if necessary. Consideration should be given to discontinuing gabapentin therapy if suicidal thoughts or behavior occur.

Acute pancreatitis

If symptoms of pancreatitis occur during gabapentin therapy, the drug should be discontinued.

Seizures

Although there is no evidence of seizure recurrence after discontinuation of gabapentin, abrupt withdrawal of anticonvulsant medications in patients with epilepsy may precipitate status epilepticus (see section "Dosage and administration").

As with other antiepileptic drugs, in some patients, the frequency of seizures may increase or new types of seizures may occur during gabapentin therapy.

Attempts to discontinue concomitant antiepileptic drugs with the aim of switching to gabapentin monotherapy in patients who were receiving multiple antiepileptic drugs have rarely been successful.

Gabapentin is not considered effective in treating primary generalized seizures such as absence seizures, and may exacerbate the frequency of such seizures in some patients. For this reason, gabapentin should be used with caution in patients with mixed seizure types that include absence seizures.

Gabapentin therapy has been associated with dizziness and somnolence, which may potentially increase the risk of accidental injuries (falls). Loss of consciousness, confusion, and development of psychiatric disturbances have also been reported. Therefore, patients should be advised to exercise caution until their individual response to gabapentin is known.

Concomitant use with opioids and other CNS depressants

Patients receiving gabapentin concomitantly with CNS depressants, including opioids, should be closely monitored for signs of CNS depression such as somnolence, sedation, and respiratory depression. Concomitant use of morphine and gabapentin may increase gabapentin concentrations. The dose of gabapentin or CNS depressants, including opioids, should be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Gabapentin should be prescribed with caution when used concomitantly with opioids due to the risk of CNS depression. In a population-based observational case-control study in patients taking opioids, concomitant use with gabapentin was associated with an increased risk of opioid-related death compared to opioid use alone (adjusted odds ratio [aOR] 1.49 [95% CI, 1.18–1.88, p < 0.001]).

Respiratory depression

Gabapentin therapy has been associated with severe respiratory depression. Patients with respiratory or neurological disorders, renal impairment, concomitant use of CNS depressants, and elderly patients are at increased risk of this serious adverse reaction. Dose adjustment may be required in such patients.

Elderly patients (over 65 years of age)

Systematic studies of gabapentin use in patients aged 65 years and older have not been conducted. In one double-blind study involving patients with neuropathic pain, somnolence, peripheral edema, and weakness occurred more frequently in patients over 65 years of age than in younger patients. Except for these findings, clinical studies in this age group did not reveal evidence of differences in the adverse event profile compared to younger patients.

Children

Due to lack of data on the long-term (beyond 36 weeks) effects of gabapentin therapy on learning ability, intellectual capacity, and child development, the benefits of long-term therapy should be weighed against its potential risks.

Misuse, abuse, and dependence

Gabapentin may cause drug dependence, which may occur even at therapeutic doses. Cases of abuse have been reported. Patients with a history of substance abuse may be at increased risk of misuse, abuse, and dependence on gabapentin and should therefore be treated with caution. A thorough assessment of the patient’s risk of misuse, abuse, or dependence should be conducted before prescribing gabapentin.

Patients receiving gabapentin therapy should be monitored for symptoms of misuse, abuse, or dependence, such as development of tolerance, dose escalation, and drug-seeking behavior.

Withdrawal symptoms

Withdrawal symptoms have been observed after discontinuation of both short- and long-term gabapentin therapy. Withdrawal symptoms may occur soon after stopping treatment, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, increased sweating, tremor, headache, depression, unusual feelings, dizziness, and malaise. The possible occurrence of withdrawal symptoms after gabapentin discontinuation may indicate drug dependence (see section "Adverse reactions"). Patients should be informed of this at the start of treatment. If discontinuation of gabapentin is required, it is recommended to do so gradually over at least one week, regardless of the indication (see section "Dosage and administration").

Laboratory tests

False-positive results may be obtained in semi-quantitative determination of total protein in urine using rapid test strips. Therefore, such test results should be confirmed using methods based on a different analytical principle, such as the biuret test, turbidimetric method, or dye-binding method, or these alternative methods should be used initially.

Use during pregnancy or breastfeeding

Pregnancy

General risks of epilepsy and antiepileptic drug (AED) use

Women of childbearing potential, especially those planning pregnancy, and pregnant women should be counseled regarding the potential risk to the fetus from both seizures and antiepileptic treatment. The need for antiepileptic therapy should be re-evaluated before pregnancy. Abrupt discontinuation of antiepileptic drugs in women being treated for epilepsy is not acceptable, as this may lead to seizures and significantly worsen the condition of both mother and child. Monotherapy should be preferred whenever possible, as polytherapy with AEDs may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the AEDs used.

Risk associated with gabapentin therapy

Gabapentin crosses the human placenta.

Data from a Scandinavian observational study involving more than 1,700 pregnant women exposed to gabapentin during the first trimester did not demonstrate an increased risk of major congenital malformations in children exposed to gabapentin in utero compared to unexposed children, or compared to children exposed to pregabalin, lamotrigine, or both pregabalin and lamotrigine. Similarly, no increased risk of nervous system disorders was observed in children exposed to gabapentin in utero.

Limited evidence suggests a higher risk of low birth weight, preterm birth, but not stillbirth, intrauterine growth restriction, low Apgar score at 5 minutes after birth, or microcephaly in children exposed to gabapentin in utero.

Animal studies have shown reproductive toxicity.

Gabapentin may be used during the first trimester of pregnancy if clinically necessary.

Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentin in utero.

Concomitant use of gabapentin and opioids during pregnancy may increase the risk of neonatal withdrawal syndrome. Newborns should be closely monitored.

Lactation period

Gabapentin passes into breast milk. Since the effect of the drug on breastfed infants has not been studied, gabapentin should be used with caution in women who are breastfeeding. The use of gabapentin in breastfeeding women is justified only if the benefit to the mother outweighs the potential risk to the infant.

Fertility

No effects on fertility were observed in animal studies.

Ability to affect reaction speed when driving or operating machinery

Gabapentin may have a minor or moderate influence on the ability to drive or operate machinery. Gabapentin affects the CNS and may cause somnolence, dizziness, or other similar symptoms. These adverse effects, even if mild or moderate, may be potentially hazardous for patients when driving vehicles or operating other machinery, particularly at the beginning of therapy and after dose escalation.

Dosage and Administration

The medicinal product is intended for oral administration.

Gabapentin may be taken with or without food. The capsule should be swallowed whole and taken with sufficient liquid (e.g., a glass of water).

For all indications, treatment should be initiated according to the dose titration schedule presented in Table 1. This titration schedule is recommended for adults and children aged 12 years and older. The dose titration schedule for children aged 6 to 12 years is described below in a separate section.

Discontinuation of gabapentin

Gabapentin should be discontinued gradually over a minimum period of 1 week, regardless of the indication.

Epilepsy

Long-term therapy is usually required in epilepsy. The dose is determined by the physician according to individual tolerability and efficacy.

Adults and children aged 12 years and older

Effective doses in epilepsy range from 900 to 3600 mg/day. Treatment should begin with dose titration as described in Table 1, or with a starting dose of 300 mg three times daily on Day 1. The dose may then be increased by 300 mg/day every 2–3 days, depending on individual tolerability and efficacy, up to a maximum dose of 3600 mg/day. Some patients may require slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

In long-term open-label clinical studies, a daily dose of 4800 mg was well tolerated by patients. The total daily dose should be divided into three doses. The maximum interval between doses should not exceed 12 hours to avoid interruptions in anticonvulsant therapy and to prevent the occurrence of seizure episodes.

Children aged 6 to 12 years

The initial dose should be 10–15 mg/kg/day. The effective dose should be achieved by titrating the drug over approximately 3 days. The effective dose of gabapentin in children aged 6 years and older is 25–35 mg/kg/day. A dose of 50 mg/kg/day was well tolerated by patients in long-term clinical studies. The total daily dose should be divided into equal parts (administered three times daily); the maximum interval between doses should not exceed 12 hours.

There is no need to monitor serum gabapentin levels. Additionally, gabapentin can be used in combination with other antiepileptic drugs, as it does not alter the plasma concentration of gabapentin or the serum concentrations of other antiepileptic drugs.

Peripheral neuropathic pain

Adults

Treatment should begin with dose titration as described in Table 1, or otherwise with a starting dose of 900 mg/day divided into three doses. The dose may then be increased by 300 mg/day every 2–3 days, depending on individual tolerability and efficacy, up to a maximum of 3600 mg/day. Some patients may require slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

The efficacy and safety of gabapentin in the treatment of peripheral neuropathic pain (e.g., painful diabetic neuropathy or postherpetic neuralgia) have not been studied in long-term clinical trials lasting more than 5 months. If a patient requires longer-term treatment (more than 5 months) with gabapentin for neuropathic pain, the physician should evaluate the patient's clinical status and determine the need for continued therapy before proceeding.

Recommendations regarding the prescription of gabapentin for all indications

In patients with poor general health or certain predisposing factors such as low body weight or post-transplant status, titration should be performed more slowly, the incremental dose reduced, or the intervals between dose increases prolonged.

Use in elderly patients (aged 65 years and older)

Elderly patients may sometimes require individual dose adjustment due to possible reduced renal function (see Table 2). Somnolence, peripheral edema, and weakness are more frequently observed in elderly patients.

Use in patients with renal impairment

Patients with marked renal impairment and those undergoing hemodialysis require individual dose adjustment (see Table 2).

Dosing in renal impairment Table 2

* The total daily dose should be divided into 3 doses. Reduced doses should be used in patients with renal impairment (creatinine clearance <79 mL/min).

** Administer at a dose of 300 mg every other day.

*** For patients with creatinine clearance <15 mL/min, the daily dose should be reduced according to creatinine clearance (e.g., patients with creatinine clearance of 7.5 mL/min should receive half of the daily dose given to patients with creatinine clearance of 15 mL/min).

Dosing for patients undergoing hemodialysis.

For anuric patients undergoing hemodialysis who have never previously received gabapentin, the recommended loading dose is 300–400 mg*, followed by 200–300 mg* of gabapentin after every 4 hours of hemodialysis. Gabapentin should not be taken on days without hemodialysis.

The maintenance dose of gabapentin for patients on hemodialysis should be determined according to Table 2.

In addition to the maintenance dose, patients on hemodialysis are recommended to take 200–300 mg* of the drug after every 4 hours of hemodialysis.

* Administer gabapentin formulations at the appropriate dosage.

Children.

Gabapentin is indicated for the treatment of epilepsy in children: as adjunctive therapy in children aged 6 years and older, and as monotherapy in children aged 12 years and older.

Overdose.

Even with intake of up to 49 g/day, no acute life-threatening toxic reactions have been reported.

Symptoms of overdose included dizziness, double vision, slurred speech, somnolence, loss of consciousness, lethargy, and mild diarrhea. All patients fully recovered with supportive treatment. Reduced absorption of gabapentin at high doses may limit absorption of other drugs and reduce toxic effects from overdose. Overdose of gabapentin, especially in combination with other CNS depressants, may result in coma.

Treatment is symptomatic. Although gabapentin can be removed by hemodialysis, this is usually not necessary. However, hemodialysis may be indicated in patients with severe renal impairment.

In studies in mice and rats, a lethal dose of gabapentin could not be determined, even with doses reaching 8000 mg/kg. Symptoms of acute toxicity in animals included ataxia, labored breathing, ptosis, decreased activity, or conversely, increased excitability.

Adverse Reactions

During epilepsy studies (adjunctive therapy or monotherapy) and neuropathic pain studies, the following adverse reactions have been reported (listed according to their frequency): very common (> 1/10), common (> 1/100 – <1/10), uncommon (> 1/1,000 – <1/100), and rare (> 1/10,000 – <1/1,000). If the frequency of adverse reactions varied across different studies, the highest reported frequency was included in the report.

Additional adverse reactions identified from post-marketing experience are categorized as "frequency not known" (cannot be estimated based on available data).

Within each frequency group, adverse effects are listed in descending order of severity.

Infections and infestations

Very common: Viral infection.

Common: Pneumonia; respiratory tract infection¹; urinary tract infection; infection, otitis media.

Blood and lymphatic system disorders

Common: Leukopenia.

Frequency not known: Thrombocytopenia.

Immune system disorders

Uncommon: Allergic reactions (e.g., urticaria).

Frequency not known: Hypersensitivity syndrome with cutaneous and systemic manifestations, which may include symptoms such as fever, rash, hepatitis, lymphadenopathy, eosinophilia, etc. (DRESS syndrome); anaphylaxis (see section "Special precautions").

Metabolism and nutrition disorders

Common: Anorexia, increased appetite.

Uncommon: Hyperglycemia (most commonly observed in patients with diabetes mellitus).

Rare: Hypoglycemia (most commonly observed in patients with diabetes mellitus).

Frequency not known: Hyponatremia.

Psychiatric disorders

Common: Hostility, confusion, emotional lability, depression, anxiety, nervousness, thinking abnormalities.

Uncommon: Agitation.

Frequency not known: Suicidal thoughts/behaviour, hallucinations, drug dependence.

Nervous system disorders

Very common: Somnolence, dizziness, ataxia.

Common: Seizures¹, hyperkinesia¹, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances (paraesthesia, hypoaesthesia), coordination difficulties, nystagmus, increased, decreased or absent reflexes.

Uncommon: Hypokinesia, thinking abnormalities.

Rare: Loss of consciousness.

Frequency not known: Other movement disorders (including choreoathetosis, dyskinesia, dystonia).

Eye disorders

Common: Vision disorders, e.g., amblyopia or diplopia.

Ear and labyrinth disorders

Common: Vertigo.

Frequency not known: Tinnitus.

Cardiac disorders

Uncommon: Palpitations.

Vascular disorders

Common: Increased blood pressure, vasodilation.

Respiratory, thoracic and mediastinal disorders

Common: Dyspnea, bronchitis, pharyngitis, cough, rhinitis.

Rare: Respiratory depression.

Gastrointestinal disorders

Common: Vomiting, nausea, dental condition changes, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence.

Uncommon: Dysphagia (difficulty swallowing).

Frequency not known: Pancreatitis².

Hepatobiliary disorders

Frequency not known: Hepatitis, jaundice.

Skin and subcutaneous tissue disorders

Common: Facial edema, purpura (most often described as bruising following trauma), rash, pruritus, acne.

Frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, eosinophilia with systemic symptoms (see section "Special precautions"), erythema multiforme, angioneurotic edema, alopecia.

Musculoskeletal and connective tissue disorders

Common: Arthralgia, myalgia, back pain, muscle spasms.

Frequency not known: Rhabdomyolysis, myoclonic seizures.

Renal and urinary disorders

Frequency not known: Acute renal failure, urinary incontinence.

Reproductive system and breast disorders

Common: Impotence.

Frequency not known: Breast enlargement, gynecomastia, sexual dysfunction (including changes in libido, ejaculation disorders, anorgasmia).

General disorders and administration site conditions

Very common: Fatigue, fever.

Common: Peripheral edema, gait disturbance, weakness, pain, discomfort, influenza-like syndrome.

Uncommon: Generalized edema.

Frequency not known: Withdrawal reactions³, chest pain. Cases of sudden death have been reported; however, a clear association with gabapentin use has not been established.

Investigations

Common: Decreased white blood cell count, weight gain.

Uncommon: Increased liver function tests (AST, ALT) and bilirubin levels.

Frequency not known: Increased creatine kinase levels⁴.

Injury, poisoning and procedural complications

Common: Accidental injury, fractures, abrasions.

Uncommon: Falls.

¹ Cases of respiratory tract infections, otitis media, seizures, and bronchitis were reported only in clinical studies involving children. Additionally, aggressive behavior and hyperkinesia were frequently observed in pediatric studies.

² Cases of acute pancreatitis have been reported during gabapentin treatment. A causal relationship with gabapentin has not been established (see section "Special precautions").

³ Withdrawal symptoms have been observed after discontinuation of both short- and long-term gabapentin therapy. Withdrawal symptoms may occur shortly after stopping treatment, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, increased sweating, tremor, headache, depression, unusual feelings, dizziness, and malaise (see section "Special precautions"). The occurrence of withdrawal symptoms after discontinuation of gabapentin may indicate drug dependence (see section "Adverse Reactions"). Patients should be informed about this at the beginning of treatment. If discontinuation of gabapentin is necessary, it is recommended to taper the dose gradually over at least one week, regardless of the indication (see section "Dosage and administration").

⁴ Cases of myopathy with elevated creatine kinase levels have been reported in patients with end-stage renal disease on hemodialysis.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 capsules in a blister. 1, 3, or 10 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer

LLC "KUSUM PHARM".

Manufacturer's address and location of operations

54 Skryabina Street, Sumy, Sumy region, 40020, Ukraine.

INSTRUCTION

for medical use of medicinal product

NEUROPENTIN®

(NUROPENTINE®)

Composition:

Active substance: gabapentin;

1 hard capsule contains 300 mg of gabapentin;

Excipients: mannite (E 421), maize starch, magnesium stearate, talc, colloidal anhydrous silicon dioxide; hard gelatin capsule: gelatin, purified water, iron oxide red (E 172), titanium dioxide (E 171).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsules of size 1 with white body and red cap, containing a white or almost white powder.

Pharmacotherapeutic group.
Antiepileptic drugs. ATC code N03A X12.

Pharmacological Properties

Pharmacodynamics

Gabapentin, 1-(aminomethyl)cyclohexaneacetic acid, is a cyclic analogue of gamma-aminobutyric acid (GABA) capable of crossing the blood-brain barrier. The anticonvulsant activity of gabapentin has been demonstrated in numerous experimental seizure models. The mechanism of gabapentin's antiepileptic action is currently unknown. Despite structural similarity to GABA, gabapentin is not a GABA mimetic, as it does not bind to either GABA_A or GABA_B receptors, does not inhibit GABA reuptake, nor does it affect GABA degradation via GABA transaminase. It does not interact with voltage-dependent sodium channels, benzodiazepine receptors, excitatory neurotransmitter binding sites, or influence catecholaminergic, acetylcholinergic, or opioid receptors. Thus, gabapentin has a completely novel mechanism of action, binding to highly specific sites within the central nervous system (CNS) that are protein in nature and predominantly localized in the neocortex, with no affinity for other antiepileptic agents.

Gabapentin is also effective in suppressing neuropathic pain.

Pharmacokinetics

Absorption is rapid. Bioavailability is approximately 60%. Bioavailability is not proportional to dose: as the dose increases, bioavailability decreases, being 60% at a dose of 300 mg and 30% at a dose of 1600 mg. Food does not affect the pharmacokinetics of gabapentin. Time to reach maximum plasma concentration is 2–3 hours. Plasma concentration of the drug is proportional to the dose. Pharmacokinetics do not change with repeated administration. Gabapentin crosses the blood-brain barrier: in patients with epilepsy, the concentration of gabapentin in cerebrospinal fluid is approximately 20% of the corresponding equilibrium plasma concentration. It passes into breast milk. Gabapentin does not bind to plasma proteins. The volume of distribution is 57.7 liters. Gabapentin is practically not metabolized. It does not induce hepatic oxidative enzymes. It is excreted unchanged by the kidneys. Elimination half-life is independent of dose and averages 5–7 hours in patients with normal renal excretory function. In elderly patients and in patients with impaired renal function, elimination rate decreases in direct proportion to creatinine clearance levels. Gabapentin is removed from blood during hemodialysis. Dose adjustment is recommended for patients with impaired renal function and for those undergoing hemodialysis.

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

Clinical characteristics.

Indications.

Epilepsy.

Gabapentin is used as an adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 6 years and older.

Gabapentin is used as monotherapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 12 years and older.

Neuropathic pain.

Gabapentin is indicated for the treatment of peripheral neuropathic pain, such as painful diabetic neuropathy and postherpetic neuralgia, in adults.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Central nervous system (CNS) depressants (including opioids)

There are data from various sources (spontaneous reports and literature) regarding cases of respiratory depression, sedation, and death following concomitant use of gabapentin with CNS depressants, including opioids. These complications have predominantly occurred when gabapentin was used concomitantly with opioids in patients who were already debilitated, elderly patients, patients with serious underlying respiratory disorders, those on multiple medications (polypharmacy), or those with substance abuse.

Morphine

In clinical studies, concomitant administration of gabapentin and morphine resulted in a 44% increase in gabapentin AUC. Therefore, patients receiving these drugs should be closely monitored for signs of CNS depression, including somnolence, sedation, and respiratory depression. If such signs occur, the dose of gabapentin or morphine should be appropriately reduced.

Antiepileptic drugs (phenobarbital, phenytoin, valproic acid, carbamazepine)

No interactions between these drugs and gabapentin have been observed.

The pharmacokinetics of steady-state plasma concentrations of gabapentin are similar in healthy volunteers and in patients with epilepsy receiving these antiepileptic agents.

Oral contraceptives containing norethindrone and/or ethinylestradiol
Concomitant administration with gabapentin does not affect the pharmacokinetics of these agents.

Antacid medicinal products containing aluminum and magnesium
Concomitant administration of these products with gabapentin reduces gabapentin bioavailability by 24%. Gabapentin should be taken no earlier than 2 hours after antacid administration.

Probenecid does not affect renal excretion of gabapentin.

Cimetidine
Concomitant administration of cimetidine with gabapentin results in a minor reduction in renal excretion of gabapentin, which is not clinically significant.

Special precautions for use

Severe skin adverse reactions (SSARs)

Severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported with gabapentin treatment. Patients should be informed of the signs and symptoms, and closely monitored for skin reactions. If signs or symptoms suggestive of these reactions occur, gabapentin should be discontinued immediately and alternative therapy considered (if necessary).

If a patient has developed a serious reaction such as SJS, TEN, or DRESS syndrome while taking gabapentin, treatment with gabapentin must never be resumed.

Anaphylaxis

Gabapentin may cause anaphylaxis. Cases of anaphylaxis have been described with symptoms including respiratory distress, swelling (of lips, throat, and tongue), hypotension, and requiring emergency intervention. Patients should be warned that if any signs of anaphylaxis occur, they must discontinue gabapentin and seek immediate medical attention.

Suicidal thoughts and behavior

Suicidal thoughts and behavior have been observed in patients treated with antiepileptic drugs for various indications. A meta-analysis of results from randomized placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior, the mechanism of which is unknown. In the post-marketing period, cases of suicidal thoughts/behavior have been reported in patients receiving gabapentin (see section "Adverse reactions").

Patients (and caregivers) should be advised to seek medical help if signs of suicidal thoughts or behavior occur. Patients taking gabapentin should be monitored for signs of suicidal thoughts and behavior, and appropriate treatment provided as needed. Consideration should be given to discontinuing gabapentin treatment if suicidal thoughts or behavior occur.

Acute pancreatitis

If symptoms of pancreatitis occur during gabapentin treatment, the drug should be discontinued.

Seizures

Although there is no evidence of seizure recurrence after stopping gabapentin, abrupt discontinuation of antiepileptic drugs in patients with epilepsy may lead to the development of status epilepticus (see section "Dosage and administration").

As with other antiepileptic drugs, in some patients, the frequency of seizures may increase or new types of seizures may occur during gabapentin treatment.

Attempts to discontinue concomitant antiepileptic drugs to switch to gabapentin monotherapy in patients previously receiving multiple antiepileptic drugs have rarely been successful.

Gabapentin is not considered effective in treating primary generalized seizures such as absence seizures, and may exacerbate the frequency of such seizures in some patients. For this reason, gabapentin should be used with caution in patients with mixed seizure types that include absence seizures.

Gabapentin treatment has been associated with dizziness and somnolence, which may potentially increase the risk of accidental injuries (falls). Loss of consciousness, confusion, and development of psychiatric disturbances have also been reported. Therefore, patients should be advised to exercise caution until their individual response to gabapentin is known.

Concomitant use with opioids and other CNS depressants

Patients receiving gabapentin concomitantly with CNS depressants, including opioids, should be closely monitored for early signs of CNS depression such as somnolence, sedation, and respiratory depression. Concomitant use of morphine and gabapentin may increase gabapentin concentrations. The dose of gabapentin or CNS depressants, including opioids, should be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Gabapentin should be prescribed with caution when used concomitantly with opioids due to the risk of CNS depression. In a population-based observational case-control study in patients taking opioids, concomitant use with gabapentin was associated with an increased risk of opioid-related death compared to opioid use alone (adjusted odds ratio (aOR) 1.49 [95% CI, 1.18–1.88, p < 0.001]).

Respiratory depression

Gabapentin treatment has been associated with severe respiratory depression. Patients with respiratory or neurological disorders, renal impairment, concomitant use of CNS depressant drugs, and elderly patients are at increased risk of this serious adverse reaction. Such patients may require dose adjustment.

Elderly patients (over 65 years of age)

Systematic studies of gabapentin use in patients aged 65 years and older have not been conducted. In one double-blind study involving patients with neuropathic pain, elderly patients (over 65 years) experienced somnolence, peripheral edema, and weakness more frequently than younger patients. Except for these findings, clinical studies in this age group have not shown evidence of differences in the adverse event profile compared to younger patients.

Children

Due to the lack of data on the long-term (over 36 weeks) effects of gabapentin therapy on learning ability, intellectual capacity, and child development, the benefits of long-term therapy should be weighed against its potential risks.

Misuse, abuse, and dependence

Gabapentin may cause medication dependence, which may occur even at therapeutic doses. Cases of abuse have been reported. Patients with a history of substance abuse may be at increased risk of gabapentin misuse, abuse, and dependence; therefore, gabapentin should be used with caution in such patients. A careful assessment of the patient's risk of misuse, abuse, or dependence should be performed before prescribing gabapentin.

Patients receiving gabapentin should be monitored for symptoms of misuse, abuse, or dependence, such as development of tolerance, dose escalation, and drug-seeking behavior.

Withdrawal symptoms

Withdrawal symptoms have been observed after discontinuation of both short- and long-term gabapentin treatment. Withdrawal symptoms may occur soon after stopping treatment, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, increased sweating, tremor, headache, depression, unusual feelings, dizziness, and malaise. The possible occurrence of withdrawal symptoms after discontinuation of gabapentin may indicate drug dependence (see section "Adverse reactions"). Patients should be informed of this at the start of treatment. If gabapentin needs to be discontinued, it is recommended to do so gradually over at least 1 week, regardless of the indication (see section "Dosage and administration").

Laboratory tests

False positive results may occur in semi-quantitative determination of total protein in urine using dipstick tests. Therefore, such dipstick test results should be confirmed using methods based on a different analytical principle, such as the biuret test, turbidimetric method, or dye-binding method, or these methods should be used initially.

Use during pregnancy or breastfeeding

Pregnancy

General risks of epilepsy and antiepileptic drug (AED) use

Women of reproductive age, especially those planning pregnancy, and pregnant women should be counseled regarding the potential risk to the fetus from both seizures and antiepileptic treatment. The need for antiepileptic therapy should be re-evaluated before pregnancy. Abrupt discontinuation of antiepileptic drugs in women being treated for epilepsy is not acceptable, as this may lead to seizures and significantly worsen the condition of both mother and child. Monotherapy should be preferred whenever possible, as polytherapy with AEDs may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the AEDs used.

Risk associated with gabapentin therapy

Gabapentin crosses the human placenta.

Data from a Scandinavian observational study involving over 1700 pregnant women who used gabapentin during the first trimester did not show an increased risk of major congenital malformations in children exposed to gabapentin in utero compared to unexposed children, or compared to children exposed to pregabalin, lamotrigine, or both. Similarly, no increased risk of nervous system disorders was observed in children exposed to gabapentin in ut游戏副本 during pregnancy.

There is limited evidence of an increased risk of low birth weight, preterm birth, but not stillbirth, intrauterine growth restriction, low Apgar score at 5 minutes after birth, or microcephaly in children exposed to gabapentin in utero.

Animal studies have shown reproductive toxicity.

Gabapentin may be used during the first trimester of pregnancy if clinically necessary.

Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentin in utero.

Concomitant use of gabapentin and opioids during pregnancy may increase the risk of neonatal withdrawal syndrome in newborns. Newborns should be closely monitored.

Breastfeeding period

Gabapentin passes into breast milk. Since the effect of the drug on breastfed infants has not been studied, gabapentin should be used with caution in breastfeeding women. Gabapentin may be used in breastfeeding women only if the benefit to the mother outweighs the potential risk to the infant.

Fertility

No effects on fertility were observed in animal studies.

Ability to affect reaction speed when driving or operating machinery

Gabapentin may have a slight or moderate effect on the ability to drive or operate machinery. Gabapentin affects the CNS and may cause somnolence, dizziness, or other similar symptoms. These adverse effects, even if mild or moderate, may be potentially hazardous for patients when driving vehicles or operating other machinery, especially at the beginning of therapy and after dose escalation.

Dosage and Administration

The medicinal product is intended for oral administration.

Gabapentin may be taken with or without food. The capsule should be swallowed whole and taken with sufficient fluid (e.g., a glass of water).

For all indications, therapy should be initiated according to the dose titration schedule presented in Table 1. This titration schedule is recommended for adults and children aged 12 years and older. The dose titration schedule for children aged 6 to 12 years is described below in a separate section.

Discontinuation of gabapentin

Gabapentin should be discontinued gradually over a minimum of 1 week, regardless of the indication.

Epilepsy

Long-term therapy is usually required for epilepsy. The dose is determined by the physician according to individual tolerability and efficacy.

Adults and children aged 12 years and older

Effective doses for epilepsy range from 900 to 3600 mg/day. Treatment should begin with dose titration as described in Table 1, or with a starting dose of 300 mg three times daily on Day 1. Thereafter, depending on individual tolerability and efficacy, the dose may be increased by 300 mg/day every 2–3 days up to a maximum dose of 3600 mg/day. Some patients may require slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

In long-term open-label clinical studies, a dose of 4800 mg/day was well tolerated by patients. The daily dose should be divided into three doses. The maximum interval between doses should not exceed 12 hours to avoid interruptions in anticonvulsant therapy and prevent seizure occurrence.

Children aged 6 to 12 years

The initial dose should be 10–15 mg/kg/day. The effective dose should be achieved by titrating the drug over approximately 3 days. The effective dose of gabapentin in children aged 6 years and older is 25–35 mg/kg/day. A dose of 50 mg/kg/day was well tolerated by patients in long-term clinical studies. The total daily dose should be divided into equal parts (administered three times daily); the maximum interval between doses should not exceed 12 hours.

Monitoring serum gabapentin levels is not required. Additionally, gabapentin can be used in combination with other antiepileptic drugs, as it does not alter the plasma concentration of gabapentin or the serum concentrations of other antiepileptic drugs.

Peripheral neuropathic pain

Adults

Treatment should begin with dose titration as described in Table 1, or otherwise with a starting dose of 900 mg/day divided into three doses. Thereafter, depending on individual tolerability and efficacy, the dose may be increased by 300 mg/day every 2–3 days up to a maximum of 3600 mg/day. Some patients may require slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

The efficacy and safety of gabapentin in the treatment of peripheral neuropathic pain (e.g., painful diabetic neuropathy or postherpetic neuralgia) have not been studied in long-term clinical trials exceeding 5 months. If a patient requires longer-term treatment (>5 months) with gabapentin for neuropathic pain, the physician should evaluate the patient's clinical status and determine the need for continued therapy before proceeding.

Recommendations regarding the use of gabapentin for all indications

In patients with poor general health or certain complicating factors such as low body weight or post-transplant status, titration should be performed more slowly, the incremental dose should be reduced, or the intervals between dose increases should be prolonged.

Use in elderly patients (aged 65 years and older)

Elderly patients may sometimes require individual dose adjustment due to possible reduced renal function (see Table 2). In elderly patients, somnolence, peripheral edema, and weakness are more frequently observed.

Use in patients with renal impairment

Patients with marked renal impairment and those undergoing hemodialysis require individual dose adjustment (see Table 2).

Dosing in renal impairment Table 2

* The total daily dose should be divided into 3 doses. Reduced doses should be used in patients with renal impairment (creatinine clearance <79 mL/min).

** Administer at a dose of 300 mg every other day.

*** For patients with creatinine clearance <15 mL/min, the daily dose should be reduced proportionally according to creatinine clearance (e.g., patients with creatinine clearance of 7.5 mL/min should receive half the daily dose of patients with creatinine clearance of 15 mL/min).

Dosing for patients undergoing hemodialysis.

For anuric patients undergoing hemodialysis who have never previously received gabapentin, the recommended initial loading dose is 300–400 mg*, followed by 200–300 mg* of gabapentin after every 4 hours of hemodialysis. Gabapentin should not be administered on days without hemodialysis.

The maintenance dose of gabapentin for patients on hemodialysis should be determined according to Table 2.

In addition to the maintenance dose, patients on hemodialysis are recommended to take 200–300 mg* of the drug after every 4 hours of hemodialysis.

* Administer gabapentin formulations at appropriate dosage strengths.

Children.

Gabapentin is indicated for the treatment of epilepsy in children: as adjunctive therapy in children aged 6 years and older, and as monotherapy in children aged 12 years and older.

Overdose.

Even with intake of up to 49 g/day, no acute life-threatening toxic reactions have been observed.

Symptoms of overdose included dizziness, double vision, slurred speech, somnolence, loss of consciousness, lethargy, and mild diarrhea. All patients fully recovered with supportive treatment. Reduced absorption of gabapentin at high doses may limit systemic absorption and reduce toxicity. Overdose with gabapentin, particularly in combination with other CNS depressants, may result in coma.

Treatment is symptomatic. Although gabapentin can be removed by hemodialysis, this is generally not necessary. However, hemodialysis may be indicated in patients with severe renal impairment.

In studies in mice and rats, the lethal dose of gabapentin could not be determined, even at doses up to 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, decreased activity, or conversely, increased excitability.

Adverse Reactions

During epilepsy studies (adjunctive therapy or monotherapy) and neuropathic pain studies, the following adverse reactions have been reported (listed according to their frequency): very common (> 1/10), common (> 1/100 – <1/10), uncommon (> 1/1,000 – <1/100), and rare (> 1/10,000 – <1/1,000). If the frequency of adverse reactions varied across different studies, the highest reported frequency was included in the report.

Additional adverse reactions identified from post-marketing surveillance are categorized as "frequency not known" (cannot be estimated based on available data).

Within each frequency group, adverse effects are listed in descending order of severity.

Infections and parasitic diseases

Very common: Viral infection.

Common: Pneumonia; respiratory infection¹; urinary tract infection; infection; otitis media.

Blood and lymphatic system disorders

Common: Leukopenia.

Frequency not known: Thrombocytopenia.

Immune system disorders

Uncommon: Allergic reactions (e.g., urticaria).

Frequency not known: Hypersensitivity syndrome with cutaneous and systemic manifestations, which may include symptoms such as fever, rash, hepatitis, lymphadenopathy, eosinophilia, etc. (DRESS syndrome); anaphylaxis (see section "Special precautions").

Metabolism and nutrition disorders

Common: Anorexia, increased appetite.

Uncommon: Hyperglycemia (most frequently observed in patients with diabetes mellitus).

Rare: Hypoglycemia (most frequently observed in patients with diabetes mellitus).

Frequency not known: Hyponatremia.

Psychiatric disorders

Common: Hostility, confusion, emotional lability, depression, anxiety, nervousness, thinking disorders.

Uncommon: Agitation.

Frequency not known: Suicidal ideation/behavior, hallucinations, drug dependence.

Nervous system disorders

Very common: Somnolence, dizziness, ataxia.

Common: Seizures¹, hyperkinesia¹, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances (paresthesia, hypesthesia), coordination disturbances, nystagmus, increased, decreased, or absent reflexes.

Uncommon: Hypokinesia, thinking disorders.

Rare: Loss of consciousness.

Frequency not known: Other movement disorders (including choreoathetosis, dyskinesia, dystonia).

Eye disorders

Common: Vision disorders, e.g., amblyopia or diplopia.

Ear and labyrinth disorders

Common: Vertigo.

Frequency not known: Tinnitus.

Cardiac disorders

Uncommon: Palpitations.

Vascular disorders

Common: Increased blood pressure, vasodilation.

Respiratory, thoracic and mediastinal disorders

Common: Dyspnea, bronchitis, pharyngitis, cough, rhinitis.

Rare: Respiratory depression.

Gastrointestinal disorders

Common: Vomiting, nausea, dental condition changes, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence.

Uncommon: Dysphagia (difficulty swallowing).

Frequency not known: Pancreatitis².

Hepatobiliary disorders

Frequency not known: Hepatitis, jaundice.

Skin and subcutaneous tissue disorders

Common: Facial edema, purpura (most often described as bruises following trauma), rash, pruritus, acne.

Frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, eosinophilia with systemic symptoms (see section "Special precautions"), erythema multiforme, angioneurotic edema, alopecia.

Musculoskeletal and connective tissue disorders

Common: Arthralgia, myalgia, back pain, muscle contractions.

Frequency not known: Rhabdomyolysis, myoclonic seizures.

Renal and urinary disorders

Frequency not known: Acute renal failure, urinary incontinence.

Reproductive system and breast disorders

Common: Impotence.

Frequency not known: Breast enlargement, gynecomastia, sexual dysfunction (including changes in libido, ejaculation disorders, anorgasmia).

General disorders and administration site conditions

Very common: Fatigue, fever.

Common: Peripheral edema, gait disturbance, weakness, pain, discomfort, influenza-like syndrome.

Uncommon: Generalized edema.

Frequency not known: Withdrawal symptoms³, chest pain. Cases of sudden death have been reported; however, a clear causal relationship with gabapentin use has not been established.

Investigations

Common: Decreased white blood cell count, weight gain.

Uncommon: Increased liver function tests (AST, ALT) and bilirubin levels.

Frequency not known: Increased creatine kinase levels⁴.

Injury, poisoning and procedural complications

Common: Accidental injury, fractures, scratches.

Uncommon: Falls.

¹ Cases of respiratory tract infections, otitis media, seizures, and bronchitis were reported only in clinical studies involving children. Additionally, aggressive behavior and hyperkinesia were relatively common in pediatric studies.

² Cases of acute pancreatitis have been reported during gabapentin therapy. A causal relationship with gabapentin has not been established (see section "Special precautions").

³ Withdrawal symptoms have been observed following discontinuation of both short- and long-term gabapentin treatment. Withdrawal symptoms may occur shortly after stopping treatment, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, increased sweating, tremor, headache, depression, unusual feelings, dizziness, and malaise (see section "Special precautions"). The emergence of withdrawal symptoms after discontinuation of gabapentin may indicate drug dependence (see section "Adverse Reactions"). Patients should be informed of this at the beginning of treatment. If discontinuation of gabapentin is necessary, it is recommended to taper the dose gradually over at least one week, regardless of the indication (see section "Dosage and administration").

⁴ Cases of myopathy associated with elevated creatine kinase levels have been reported in patients with end-stage renal disease undergoing hemodialysis.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 capsules in a blister. 1, 3, or 10 blisters in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and site of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

INSTRUCTIONS

for medical use of the medicinal product

NUROPENTINE®

(NUROPENTINE®)

Composition:

Active substance: gabapentin;

1 hard capsule contains 300 mg of gabapentin;

Excipients: mannitol (E 421), maize starch, magnesium stearate, talc, colloidal anhydrous silicon dioxide; hard gelatin capsule: gelatin, purified water, iron oxide red (E 172), titanium dioxide (E 171).

Dosage form. Hard capsules.

Main physicochemical properties: size 1 hard gelatin capsules with white body and red cap, containing a white or almost white powder.

Pharmacotherapeutic group.

Antiepileptic drugs. ATC code N03A X12.

Pharmacological Properties

Pharmacodynamics

Gabapentin – 1-(aminomethyl)cyclohexaneacetic acid – is a cyclic analogue of gamma-aminobutyric acid (GABA) capable of crossing the blood-brain barrier. The anticonvulsant activity of gabapentin has been demonstrated in numerous experimental seizure models. The mechanism of gabapentin's antiepileptic action is currently unknown. Despite structural similarity to GABA, gabapentin is not a GABA mimetic, as it does not bind to either GABA_A or GABA_B receptors, does not inhibit GABA reuptake, nor does it affect GABA degradation via GABA-transaminase. It does not interact with voltage-dependent sodium channels, benzodiazepine receptors, excitatory neurotransmitter binding sites, or influence catecholaminergic, cholinergic, or opioid receptors. Thus, gabapentin has a completely novel mechanism of action, binding to highly specific sites in the central nervous system (CNS) of protein nature, predominantly localized in the neocortex, which have no affinity for other antiepileptic drugs.

Gabapentin is also effective in suppressing neuropathic pain.

Pharmacokinetics

Absorption is rapid. Bioavailability is approximately 60%. Bioavailability is not proportional to dose: as the dose increases, bioavailability decreases, being 60% at a dose of 300 mg and 30% at a dose of 1600 mg. Food does not affect the pharmacokinetics of gabapentin. Time to reach maximum concentration is 2–3 hours. Plasma concentration of the drug is proportional to the dose. Pharmacokinetics do not change with repeated administration. It crosses the blood-brain barrier: in patients with epilepsy, the concentration of gabapentin in cerebrospinal fluid is approximately 20% of the corresponding steady-state plasma concentration. It passes into breast milk. Gabapentin does not bind to plasma proteins; the volume of distribution is 57.7 liters. Gabapentin is practically not metabolized. It does not induce hepatic oxidative enzymes. It is excreted by the kidneys unchanged. Elimination half-life is independent of dose and averages 5–7 hours in patients with normal renal excretory function. In elderly patients and in patients with impaired renal function, elimination rate decreases proportionally to creatinine clearance levels. It is removed from the blood during hemodialysis. Dose adjustment is recommended for patients with impaired renal function and for patients undergoing hemodialysis.

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

Clinical characteristics.

Indications.

Epilepsy.

Gabapentin is used as an adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 6 years and older.

Gabapentin is used as monotherapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 12 years and older.

Neuropathic pain.

Gabapentin is indicated for the treatment of peripheral neuropathic pain, such as painful diabetic neuropathy and postherpetic neuralgia, in adults.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Central nervous system (CNS) depressants (including opioids)

Data from various sources (spontaneous reports and literature) indicate cases of respiratory depression, sedation, and death with concomitant use of gabapentin and CNS depressants, including opioids. These complications were mostly observed when gabapentin was used concomitantly with opioids in patients who were already weakened, elderly patients, or those with serious underlying respiratory disorders, polypharmacy, or substance abuse.

Morphine

In clinical studies, concomitant administration of gabapentin and morphine resulted in a 44% increase in gabapentin AUC. Therefore, patients receiving these drugs should be closely monitored for signs of CNS depression, such as somnolence, sedative effects, and respiratory depression. If such signs occur, the dose of gabapentin or morphine should be appropriately reduced.

Antiepileptic drugs (phenobarbital, phenytoin, valproic acid, carbamazepine)

No interactions between these drugs and gabapentin have been observed.

The pharmacokinetics of steady-state plasma concentrations of gabapentin are similar in healthy volunteers and in patients with epilepsy receiving these antiepileptic agents.

Oral contraceptives containing norethindrone and/or ethinylestradiol
Concomitant administration with gabapentin does not affect the pharmacokinetics of these agents.

Antacid medicinal products containing aluminium and magnesium
Concomitant administration of these products with gabapentin results in a 24% reduction in gabapentin bioavailability. Gabapentin should be taken no earlier than 2 hours after antacid administration.

Probenecid does not affect renal excretion of gabapentin.

Cimetidine
Concomitant administration of cimetidine with gabapentin results in a minor reduction in renal excretion of gabapentin, which is not clinically significant.

Special precautions for use

Severe skin adverse reactions (SSARs)

Severe skin adverse reactions (SSARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or lead to fatal outcomes, have been reported in association with gabapentin therapy. Patients should be informed about the signs and symptoms of these reactions, and skin reactions should be closely monitored. If signs or symptoms suggestive of these reactions occur, gabapentin should be discontinued immediately, and alternative therapy should be considered (if necessary).

If a serious reaction such as SJS, TEN, or DRESS syndrome develops during treatment with gabapentin, re-administration of gabapentin must never be attempted.

Anaphylaxis

Gabapentin may cause anaphylaxis. Cases of anaphylaxis have been described, presenting with respiratory distress, swelling (of lips, throat, and tongue), hypotension, and requiring emergency intervention. Patients should be warned that if any signs of anaphylaxis occur, they must discontinue gabapentin and seek immediate medical attention.

Suicidal thoughts and behavior

Suicidal thoughts and behavior have been observed in patients treated with antiepileptic drugs for various indications. A meta-analysis of results from randomized, placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior, the mechanism of which is unknown. In the post-marketing period, cases of suicidal thoughts/behavior have been reported in patients receiving gabapentin (see section "Adverse reactions").

Patients (and caregivers) should be advised to seek medical help if signs of suicidal thoughts or behavior occur. Patients receiving gabapentin should be monitored for the emergence of suicidal thoughts and behavior, and appropriate treatment should be initiated as needed. Consideration should be given to discontinuing gabapentin therapy if suicidal thoughts or behavior occur.

Acute pancreatitis

If symptoms of pancreatitis occur during gabapentin therapy, the drug should be discontinued.

Seizures

Although there is no evidence of seizure recurrence after discontinuation of gabapentin, abrupt withdrawal of antiepileptic drugs in patients with epilepsy may precipitate status epilepticus (see section "Dosage and administration").

As with other antiepileptic drugs, in some patients, the frequency of seizures may increase or new types of seizures may occur during gabapentin therapy.

Attempts to discontinue concomitant antiepileptic drugs with the aim of switching to gabapentin monotherapy in patients previously receiving multiple antiepileptic drugs have rarely been successful.

Gabapentin is not considered effective for the treatment of primary generalized seizures such as absence seizures, and it may exacerbate the severity of such seizures in some patients. For this reason, gabapentin should be used with caution in patients with mixed seizure types that include absence seizures.

Gabapentin therapy has been associated with dizziness and somnolence, which may potentially increase the risk of accidental injuries (e.g., falls). Loss of consciousness, confusion, and development of psychiatric disorders have also been reported. Therefore, patients should be advised to exercise caution until their individual response to gabapentin is known.

Concomitant use with opioids and other CNS depressants

Patients receiving gabapentin concomitantly with CNS depressants, including opioids, should be closely monitored for early signs of CNS depression, such as somnolence, sedation, and respiratory depression. Concomitant use of morphine and gabapentin may increase gabapentin concentrations. The dose of gabapentin or CNS depressants, including opioids, should be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Gabapentin should be prescribed with caution when used concomitantly with opioids due to the risk of CNS depression. In a population-based observational case-control study of patients taking opioids, concomitant use of gabapentin was associated with an increased risk of opioid-related death compared to opioid use alone (adjusted odds ratio [aOR] 1.49 [95% CI, 1.18–1.88, p < 0.001]).

Respiratory depression

Gabapentin therapy has been associated with severe respiratory depression. Patients with respiratory or neurological disorders, renal impairment, concomitant use of CNS depressants, and elderly patients are at increased risk for this serious adverse reaction. Dose adjustment may be required in such patients.

Elderly patients (aged 65 years and older)

Systematic studies of gabapentin use in patients aged 65 years and older have not been conducted. In one double-blind study involving patients with neuropathic pain, elderly patients (aged over 65 years) more frequently developed somnolence, peripheral edema, and weakness compared to younger patients. Except for these findings, clinical studies in this age group have not revealed evidence of differences in the adverse event profile compared to that in younger patients.

Children

Due to the lack of data on the long-term (beyond 36 weeks) effects of gabapentin therapy on learning ability, intellectual capacity, and development in children, the benefits of long-term therapy should be weighed against its potential risks.

Misuse, abuse, and dependence

Gabapentin may cause medication dependence, which may occur even at therapeutic doses. Cases of abuse have been reported. Patients with a history of substance abuse may be at increased risk of gabapentin misuse, abuse, and dependence; therefore, gabapentin should be used with caution in such patients. A careful assessment of the patient's risk of misuse, abuse, or dependence should be performed before prescribing gabapentin.

Patients receiving gabapentin therapy should be monitored for symptoms of misuse, abuse, or dependence, such as the development of tolerance, dose escalation, and drug-seeking behavior.

Withdrawal symptoms

Withdrawal symptoms have been observed after discontinuation of both short- and long-term gabapentin therapy. Withdrawal symptoms may occur shortly after discontinuation, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, increased sweating, tremor, headache, depression, unusual feelings, dizziness, and malaise. The possible occurrence of withdrawal symptoms after gabapentin discontinuation may indicate drug dependence (see section "Adverse reactions"). Patients should be informed about this at the beginning of therapy. If gabapentin needs to be discontinued, it is recommended to do so gradually over at least 1 week, regardless of the indication (see section "Dosage and administration").

Laboratory tests

False-positive results may be obtained when semi-quantitative determination of total protein in urine is performed using dipstick tests. Therefore, such dipstick test results should be confirmed using methods based on a different analytical principle, such as the biuret test, turbidimetric method, or dye-binding method, or these alternative methods should be used initially.

Use during pregnancy or breastfeeding

Pregnancy

General risks of epilepsy and use of antiepileptic drugs (AEDs)

Women of childbearing potential, especially those planning pregnancy, and pregnant women should be counseled regarding the potential risk to the fetus from both seizures and antiepileptic drug therapy. The need for antiepileptic therapy should be re-evaluated before pregnancy. Abrupt discontinuation of antiepileptic drugs in women being treated for epilepsy is not acceptable, as it may lead to seizures and significantly worsen the condition of both mother and child. Monotherapy should be preferred whenever possible, as polytherapy with AEDs may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the AEDs used.

Risk associated with gabapentin therapy

Gabapentin crosses the human placenta.

Data from a Scandinavian observational study involving more than 1,700 pregnant women who used gabapentin during the first trimester did not demonstrate an increased risk of major congenital malformations in children exposed to gabapentin in utero compared to unexposed children, or compared to children exposed to pregabalin, lamotrigine, or both pregabalin and lamotrigine. Similarly, no increased risk of nervous system disorders was observed in children exposed to gabapentin in utero.

There is limited evidence of an increased risk of low birth weight, preterm birth, but not stillbirth, intrauterine growth restriction, low Apgar score at 5 minutes after birth, or microcephaly in children exposed to gabapentin in utero.

Animal studies have shown reproductive toxicity.

Gabapentin may be used during the first trimester of pregnancy if there is a clinical need.

Neonatal withdrawal syndrome has been reported in newborns exposed to gabapentin in utero.

Concomitant use of gabapentin and opioids during pregnancy may increase the risk of neonatal withdrawal syndrome in newborns. Newborns should be closely monitored.

Lactation

Gabapentin passes into breast milk. Since the effect of the drug on breastfed infants has not been studied, gabapentin should be used with caution in breastfeeding women. The use of gabapentin in breastfeeding women is justified only if the benefit to the mother outweighs the potential risk to the infant.

Fertility

No effects on fertility were observed in animal studies.

Ability to affect reaction speed when driving or operating machinery

Gabapentin may have a minor or moderate influence on the ability to drive or operate machinery. Gabapentin affects the CNS and may cause somnolence, dizziness, or other similar symptoms. These adverse effects, even if mild or moderate, may be potentially hazardous for patients when driving vehicles or operating other machines, especially at the beginning of therapy and after dose escalation.

Method of administration and dosage.

The medicinal product is intended for oral administration.

Gabapentin may be taken with or without food. The capsule should be swallowed whole and taken with sufficient fluid (e.g., a glass of water).

For all indications, treatment should be initiated according to the dose titration schedule presented in Table 1. This schedule is recommended for adults and children aged 12 years and older. The dose titration regimen for children aged 6 to 12 years is described separately in the subsection below.

Discontinuation of gabapentin

Gabapentin should be discontinued gradually over a minimum of 1 week, regardless of the indication.

Epilepsy

Long-term therapy is usually required in epilepsy. The dose is determined by the physician according to individual tolerability and efficacy.

Adults and children aged 12 years and older

Effective doses in epilepsy range from 900 to 3600 mg/day. Treatment should begin with dose titration as described in Table 1, or with a dose of 300 mg three times daily on Day 1. Then, depending on individual tolerability and efficacy, the dose may be increased by 300 mg/day every 2–3 days up to the maximum dose of 3600 mg/day. Some patients may require slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

In long-term open-label clinical studies, a dose of 4800 mg/day was well tolerated by patients. The daily dose should be divided into three administrations. The maximum interval between doses should not exceed 12 hours to avoid interruptions in anticonvulsant therapy and prevent seizure occurrence.

Children aged 6 to 12 years

The initial dose should be 10–15 mg/kg/day. The effective dose should be achieved by titrating the drug over approximately 3 days. The effective dose of gabapentin in children aged 6 years and older is 25–35 mg/kg/day. A dose of 50 mg/kg/day was well tolerated by patients in long-term clinical studies. The total daily dose should be divided into equal parts (administered three times daily); the maximum interval between doses should not exceed 12 hours.

There is no need to monitor serum gabapentin levels. Additionally, gabapentin can be used in combination with other antiepileptic drugs, as it does not alter the plasma concentration of gabapentin or serum concentrations of other antiepileptic drugs.

Peripheral neuropathic pain

Adults

Treatment should begin with dose titration as described in Table 1; otherwise, the initial dose of 900 mg/day should be divided into three doses. Then, depending on individual tolerability and efficacy, the dose may be increased by 300 mg/day every 2–3 days up to the maximum of 3600 mg/day. Some patients may require slower titration of gabapentin. The shortest time to reach a dose of 1800 mg/day is 1 week, 2400 mg/day is 2 weeks, and 3600 mg/day is 3 weeks.

The efficacy and safety of gabapentin in the treatment of peripheral neuropathic pain (e.g., painful diabetic neuropathy or postherpetic neuralgia) have not been studied in long-term clinical trials lasting more than 5 months. If a patient requires longer-term treatment (more than 5 months) with gabapentin for neuropathic pain, the physician should evaluate the patient's clinical status and determine the need for continued therapy before proceeding.

Recommendations regarding the use of gabapentin for all indications

Patients with poor general health or certain predisposing factors, such as low body weight or post-transplant status, may require slower titration, reduced incremental dose steps, or longer intervals between dose increases.

Use in elderly patients (aged 65 years and older)

Elderly patients may sometimes require individual dose adjustment due to possible reduced renal function (see Table 2). In elderly patients, somnolence, peripheral edema, and weakness are more frequently observed.

Use in patients with renal impairment

Patients with marked renal impairment and those on hemodialysis require individual dose adjustment of the drug (see Table 2).

Dosing in renal impairment Table 2

* The total daily dose should be divided into 3 doses. Reduced doses should be used in patients with renal impairment (creatinine clearance <79 mL/min).

** Administer at a dose of 300 mg every other day.

*** For patients with creatinine clearance <15 mL/min, the daily dose should be reduced according to creatinine clearance (e.g., patients with creatinine clearance of 7.5 mL/min should receive half of the daily dose given to patients with creatinine clearance of 15 mL/min).

Dosing for patients undergoing hemodialysis.

For anuric patients undergoing hemodialysis who have never previously received gabapentin, the recommended loading dose is 300–400 mg*, followed by 200–300 mg* of gabapentin after every 4 hours of hemodialysis. Gabapentin should not be administered on days without hemodialysis.

The maintenance dose of gabapentin for patients on hemodialysis should be determined according to Table 2.

In addition to the maintenance dose, patients on hemodialysis are recommended to take 200–300 mg* of the drug after every 4 hours of hemodialysis.

* Administer gabapentin formulations at appropriate dosage strengths.

Children.

Gabapentin is indicated for the treatment of epilepsy in children: as adjunctive therapy in children aged 6 years and older, and as monotherapy in children aged 12 years and older.

Overdose.

Even with intake of up to 49 g/day, acute life-threatening toxic reactions have not been observed.

Symptoms of overdose included dizziness, double vision, slurred speech, somnolence, loss of consciousness, lethargy, and mild diarrhea. All patients fully recovered with supportive treatment. Reduced absorption of gabapentin at high doses may limit absorption of other drugs and reduce toxicity from overdose. Overdose of gabapentin, particularly in combination with other CNS depressants, may result in coma.

Treatment is symptomatic. Although gabapentin can be removed by hemodialysis, this is usually not necessary. However, hemodialysis may be indicated in patients with severe renal impairment.

In studies in mice and rats, the lethal dose of gabapentin could not be determined, even at doses up to 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, decreased activity, or conversely, increased excitability.

Adverse Reactions

During epilepsy studies (adjunctive therapy or monotherapy) and neuropathic pain studies, the following adverse reactions have been reported (listed according to their frequency): very common (> 1/10), common (> 1/100 – <1/10), uncommon (> 1/1,000 – <1/100), and rare (> 1/10,000 – <1/1,000). If the frequency of adverse reactions varied across different studies, the highest reported frequency was included in the report.

Additional adverse reactions identified from post-marketing experience are categorized as "frequency not known" (cannot be estimated based on available data).

Within each frequency group, adverse effects are listed in descending order of severity.

Infections and parasitic diseases

Very common: Viral infection.

Common: Pneumonia; respiratory infection¹; urinary tract infection; infection, otitis media.

Blood and lymphatic system disorders

Common: Leukopenia.

Frequency not known: Thrombocytopenia.

Immune system disorders

Uncommon: Allergic reactions (e.g., urticaria).

Frequency not known: Hypersensitivity syndrome with cutaneous and systemic manifestations, which may include symptoms such as fever, rash, hepatitis, lymphadenopathy, eosinophilia, etc. (DRESS syndrome); anaphylaxis (see section "Special precautions").

Metabolism and nutrition disorders

Common: Anorexia, increased appetite.

Uncommon: Hyperglycemia (most commonly observed in patients with diabetes mellitus).

Rare: Hypoglycemia (most commonly observed in patients with diabetes mellitus).

Frequency not known: Hyponatremia.

Psychiatric disorders

Common: Hostility, confusion, emotional lability, depression, anxiety, nervousness, thinking abnormalities.

Uncommon: Agitation.

Frequency not known: Suicidal thoughts/behaviour, hallucinations, drug dependence.

Nervous system disorders

Very common: Somnolence, dizziness, ataxia.

Common: Seizures¹, hyperkinesia¹, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances (paraesthesia, hypaesthesia), coordination disturbances, nystagmus, increased, decreased or absent reflexes.

Uncommon: Hypokinesia, thinking abnormalities.

Rare: Loss of consciousness.

Frequency not known: Other movement disorders (including choreoathetosis, dyskinesia, dystonia).

Eye disorders

Common: Vision disorders, e.g., amblyopia or diplopia.

Ear and labyrinth disorders

Common: Vertigo.

Frequency not known: Tinnitus.

Cardiac disorders

Uncommon: Palpitations.

Vascular disorders

Common: Increased blood pressure, vasodilation.

Respiratory, thoracic and mediastinal disorders

Common: Dyspnea, bronchitis, pharyngitis, cough, rhinitis.

Rare: Respiratory depression.

Gastrointestinal disorders

Common: Vomiting, nausea, dental condition changes, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence.

Uncommon: Dysphagia (difficulty swallowing).

Frequency not known: Pancreatitis².

Hepatobiliary disorders

Frequency not known: Hepatitis, jaundice.

Skin and subcutaneous tissue disorders

Common: Facial edema, purpura (most commonly described as bruising after trauma), rash, pruritus, acne.

Frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, eosinophilia with systemic symptoms (see section "Special precautions"), erythema multiforme, angioneurotic edema, alopecia.

Musculoskeletal and connective tissue disorders

Common: Arthralgia, myalgia, back pain, muscle contractions.

Frequency not known: Rhabdomyolysis, myoclonic seizures.

Renal and urinary disorders

Frequency not known: Acute renal failure, urinary incontinence.

Reproductive system and breast disorders

Common: Impotence.

Frequency not known: Breast enlargement, gynecomastia, sexual dysfunction (including changes in libido, ejaculation disorders, anorgasmia).

General disorders and administration site conditions

Very common: Fatigue, fever.

Common: Peripheral edema, gait disturbance, weakness, pain, discomfort, influenza-like syndrome.

Uncommon: Generalized edema.

Frequency not known: Withdrawal reactions³, chest pain. Cases of sudden death have been reported, although a clear causal relationship with gabapentin use has not been established.

Investigations

Common: Decreased white blood cell count, weight gain.

Uncommon: Increased liver function tests (AST, ALT) and bilirubin levels.

Frequency not known: Increased creatine kinase levels⁴.

Injury and poisoning

Common: Accidental injury, fractures, lacerations.

Uncommon: Falls.

¹ Cases of respiratory tract infections, otitis media, seizures, and bronchitis were reported only in clinical studies involving children. Additionally, aggressive behavior and hyperkinesia were frequently observed in pediatric studies.

² Cases of acute pancreatitis have been reported during gabapentin therapy. A causal relationship with gabapentin has not been established (see section "Special precautions").

³ Withdrawal symptoms have been observed after discontinuation of both short- and long-term gabapentin treatment. Withdrawal symptoms may occur shortly after stopping treatment, usually within 48 hours. Most commonly reported symptoms include anxiety, insomnia, nausea, pain, increased sweating, tremor, headache, depression, unusual feelings, dizziness, and malaise (see section "Special precautions"). The emergence of withdrawal symptoms after discontinuation of gabapentin may indicate drug dependence (see section "Adverse Reactions"). Patients should be informed about this at the beginning of treatment. If discontinuation of gabapentin is necessary, it is recommended to taper the dose gradually over at least one week, regardless of the indication (see section "Dosage and administration").

⁴ Cases of myopathy with elevated creatine kinase levels have been reported in patients with end-stage renal disease undergoing hemodialysis.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 capsules in a blister. 1, 3, or 10 blisters per cardboard package.

Prescription status. Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and site of operations.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.