Neuralgin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEURALGIN (Neuralgin)

Composition:

Active substance: gabapentin;

1 capsule contains 100 mg or 300 mg or 400 mg of gabapentin;

Excipients: anhydrous lactose, maize starch, talc;

Capsule shell:

100 mg capsules – gelatin, titanium dioxide (E 171);

300 mg capsules – gelatin, titanium dioxide (E 171), colouring agent D&C Yellow No. 10 (quinoline yellow E 104);

400 mg capsules – gelatin, titanium dioxide (E 171), colouring agent D&C Yellow No. 10 (quinoline yellow E 104), colouring agent FD&C Red No. 40 (E 129).

Pharmaceutical form. Capsules.

Main physicochemical properties:

100 mg capsules

Hard gelatin capsules, size 3, "Conisnap", body and cap white in colour with a matte surface. In blue lettering on the cap: "Gabapentin/100 mg", and on the body: the logo "R" or without logo, or no inscriptions on either cap or body. Capsules are filled with white powder.

300 mg capsules

Hard gelatin capsules, size 1, "Conisnap", body and cap yellow in colour with a matte surface. In blue lettering on the cap: "Gabapentin/300 mg", and on the body: the logo "R" or without logo, or no inscriptions on either cap or body. Capsules are filled with white powder.

400 mg capsules

Hard gelatin capsules, size 0, "Conisnap", body and cap orange in colour with a matte surface. In blue lettering on the cap: "Gabapentin/400 mg", and on the body: the logo "R" or without logo, or no inscriptions on either cap or body. Capsules are filled with white powder.

Pharmacotherapeutic group.

Antiepileptic agents. ATC code N03A X12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Gabapentin readily crosses into the brain and prevented seizures in a number of animal models of epilepsy. Gabapentin does not alter the metabolism of GABA (gamma-aminobutyric acid) and has no affinity for GABA_A or GABA_B receptors. It does not bind to other neurotransmitter receptors in the brain and does not interact with sodium channels. Gabapentin binds with high affinity to the α2-δ (alpha2-delta) subunit of voltage-dependent calcium channels, which is presumed to underlie its anticonvulsant effect in animals. Broad-spectrum screening studies have not identified any other targets for gabapentin besides α2-δ.

Data from several preclinical studies suggest that the pharmacological activity of gabapentin may be mediated through binding to the α2-δ subunit, resulting in reduced release of excitatory neurotransmitters in various regions of the central nervous system (CNS). This mechanism may contribute to the anticonvulsant effect of gabapentin; however, its role in producing this effect in humans has not been established.

Gabapentin has also demonstrated efficacy in several preclinical animal models of pain. It is hypothesized that the specific binding of gabapentin to the α2-δ subunit produces several distinct effects that may contribute to its analgesic activity in animal pain models. Gabapentin may exert analgesic effects both at the spinal cord level and in higher brain centers by interacting with descending inhibitory pathways of pain sensitivity. The contribution of these mechanisms to the clinical efficacy of gabapentin in humans has not been established.

Clinical efficacy and safety

Clinical trials of adjunctive therapy for partial seizures in children aged 3 to 12 years showed a numerically higher, but statistically non-significant, response rate of 50% in favor of gabapentin compared to placebo. A post-hoc analysis of responder rates by age did not reveal a significant age effect using either continuous or binary variables (age groups 3–5 years and 6–12 years). The results of this analysis are presented in Table 1.

Table 1

Response rate to treatment (≥ 50 % improvement) by treatment categories and groups. MITT population*
Age category	Placebo	Gabapentin	P-value
< 6 years	4/21 (19.0 %)	4/17 (23.5 %)	0.7362
6-12 years	17/99 (17.2 %)	20/96 (20.8 %)	0.5144

* MITT (modified intent-to-treat population, including all patients who received at least one dose of either treatment) includes all randomized patients who adequately completed daily seizure diaries for at least 28 days during the baseline and double-blind phases.

Pharmacokinetics.

Absorption

After oral administration of gabapentin, maximum plasma concentration (Cmax) is reached within 2 to 3 hours. There is a trend toward decreased bioavailability (fraction of the dose absorbed) of gabapentin with increasing dose. Absolute bioavailability of gabapentin following administration of 300 mg capsules is approximately 60%. Co-administration with food, including high-fat meals, does not have a clinically significant effect on the pharmacokinetics of gabapentin.

Repeated dosing does not affect the pharmacokinetics of gabapentin. Although plasma concentrations of gabapentin varied between 2 and 20 mcg/mL in clinical trials, this parameter did not determine the efficacy and safety of the drug.

Pharmacokinetic parameters are presented in Table 2.

Table 2

Summary of mean (%CV) steady-state pharmacokinetic parameters after
administration of the drug every 8 hours

Pharmacokinetic parameter	300 mg (N=7)		400 mg (N=14)		800 mg (N=14)
	Mean	%CV	Mean	%CV	Mean	%CV
Cmax (μg/mL)	4.02	(24)	5.74	(38)	8.71	(29)
tmax (h)	2.7	(18)	2.1	(54)	1.6	(76)
T1/2 (h)	5.2	(12)	10.8	(89)	10.6	(41)
AUC (0-8) (μg•h/mL)	24.8	(24)	34.5	(34)	51.4	(27)
Ae% (%)	ND	ND	47.2	(25)	34.4	(37)

Cmax = maximum steady-state plasma concentration;

tmax = time to reach Cmax;

T1/2 = elimination half-life;

AUC (0–8) = steady-state area under the pharmacokinetic concentration–time curve from time 0 to 8 hours after drug administration;

Ae% = percentage of the administered dose excreted unchanged in urine from time 0 to 8 hours after drug administration;

ND = not available.

Distribution

Gabapentin does not bind to plasma proteins. The volume of distribution of the drug is 57.7 L. The concentration of gabapentin in cerebrospinal fluid (CSF) of patients with epilepsy is approximately 20% of the steady-state minimum plasma concentration. Gabapentin passes into breast milk.

Biotransformation

There are no data on gabapentin metabolism in humans. The drug does not induce liver oxidative enzymes involved in drug metabolism.

Elimination

Gabapentin is excreted exclusively by the kidneys in unchanged form. The elimination half-life of gabapentin is independent of dose and averages 5–7 hours.

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

Gabapentin is removed from plasma during hemodialysis. Dose adjustment is recommended for patients with impaired renal function or those undergoing hemodialysis (see section "Dosage and administration").

The pharmacokinetics of gabapentin in children was evaluated in 50 healthy volunteers aged 1 month to 12 years. Overall, when dose was normalized per kilogram of body weight (mg/kg), plasma concentrations of gabapentin in children aged 5 years and older were similar to those in adults.

In a pharmacokinetic study of 24 healthy children aged 1 to 48 months, AUC was approximately 30% lower, Cmax was lower, and clearance normalized per unit of body weight was higher compared to data obtained in children aged 5 years and older.

Linearity/Non-linearity

The bioavailability of gabapentin (fraction absorbed) decreases with increasing dose, indicating non-linear pharmacokinetics of the drug, specifically bioavailability-related parameters (F): Ae%, CL/F, Vd/F. Elimination pharmacokinetics (parameters not including F, such as CLr and T1/2) follows a linear pattern. The steady-state plasma concentration of gabapentin is predictable based on data from single-dose administration.

Clinical characteristics.

Indications.

Epilepsy

As adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 6 years and older.

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

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 of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Cases of respiratory depression and/or sedation associated with concomitant use of gabapentin and opioids have been reported in spontaneous reports and in the literature. In some reports, particular concern has been expressed regarding the use of gabapentin-opioid combinations, especially in elderly patients.

In a study involving healthy volunteers (N=12), administration of 60 mg controlled-release morphine capsules 2 hours before 600 mg gabapentin capsules resulted in a 44% increase in mean AUC of gabapentin compared to gabapentin administered without morphine. For this reason, patients should be carefully monitored for signs of central nervous system (CNS) depression such as somnolence; the dose of gabapentin or morphine should be appropriately reduced.

No interactions between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine have been observed.

Gabapentin pharmacokinetics are similar in healthy volunteers and in patients with epilepsy who are taking these antiepileptic drugs.

Concomitant administration of gabapentin and oral contraceptives containing norethisterone and/or ethinylestradiol does not affect the steady-state concentrations of these agents.

Antacids containing Al³⁺ and Mg²⁺ reduce gabapentin bioavailability by approximately 20%; therefore, gabapentin should be administered at least 2 hours after antacid administration.

Myelotoxic medicinal products potentiate hematotoxicity (leukopenia).

Renal excretion of gabapentin is not altered by probenecid.

A weak decrease in renal clearance of gabapentin has been observed when administered concomitantly with cimetidine, although this is not expected to be of clinical significance.

Gabapentin pharmacokinetics are similar in healthy volunteers and in patients with epilepsy receiving antiepileptic agents.

Special precautions for use.

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome)

Severe, life-threatening systemic hypersensitivity reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS), have been reported in patients taking medications, including gabapentin (see section "Adverse reactions").

It is important to note that early signs of hypersensitivity, such as fever or lymphadenopathy, may appear before the onset of rash. If such symptoms occur, gabapentin treatment should be discontinued immediately unless an alternative cause for the symptoms has been established.

Severe skin adverse reactions (SSAR)

Severe skin adverse reactions (SSAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported in association with gabapentin therapy. During treatment initiation, patients should be informed about the signs and symptoms of these reactions 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 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. In reported cases, symptoms included dyspnea, swelling of lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue gabapentin immediately and seek emergency medical help if symptoms of anaphylaxis occur (see section "Adverse reactions").

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 is unknown, but available data do not exclude a potential influence of gabapentin.

Therefore, signs of suicidal thoughts and behavior should be monitored, and appropriate therapy considered. Patients (and caregivers) should be advised to contact their physician immediately if suicidal thoughts or behaviors occur.

Acute pancreatitis

Gabapentin should be discontinued if acute pancreatitis occurs during treatment (see section "Adverse reactions").

Seizures

Although there is no evidence of rebound seizures, abrupt discontinuation of anticonvulsant therapy may precipitate status epilepticus.

As with other anticonvulsant drugs, in some patients receiving gabapentin, seizure frequency may increase or new types of seizures may appear.

Attempts to discontinue concomitant antiepileptic drugs to switch to gabapentin monotherapy in refractory patients receiving multiple antiepileptic drugs are rarely successful.

Gabapentin is not considered effective in the treatment of primary generalized seizures, such as absence seizures, and may even exacerbate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizure types, including absence seizures.

Dizziness, somnolence, loss of consciousness, and cognitive impairment

Gabapentin therapy has been associated with dizziness and somnolence, which may lead to accidental injuries (due to falls). Post-marketing data have reported cases of confusion, loss of consciousness, and cognitive disturbances. Therefore, patients should be advised to exercise caution until they become familiar with the potential effects of the drug.

Concomitant use with opioids

Increased gabapentin concentrations may occur in patients requiring concomitant opioid therapy. Therefore, patients should be monitored for signs of CNS depression, such as somnolence, sedation, and respiratory depression. The dose of gabapentin or opioids should be appropriately reduced (see section "Interaction with other medicinal products and other forms of interaction").

Respiratory depression

Gabapentin has been associated with severe respiratory depression. The risk of severe respiratory depression is increased in patients with respiratory impairment, respiratory or neurological disorders, renal insufficiency, concomitant use of CNS depressants, and in elderly patients. These patients may require dose adjustments.

Elderly patients (aged 65 years and older)

Systematic studies on the use of gabapentin in patients aged 65 years and older have not been conducted. In one double-blind study in patients with neuropathic pain, somnolence, peripheral edema, and asthenia occurred somewhat more frequently in patients aged 65 years and older compared to younger patients. Apart from these findings, no differences in the adverse effect profile were observed in clinical trials between this age group and younger patients.

Children

The long-term impact (beyond 36 weeks) of gabapentin therapy on learning ability, intelligence, and development in children and adolescents has not been adequately studied. Therefore, the benefits of long-term therapy should be weighed against the potential risks of such treatment.

Improper use, 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 have an increased risk of improper use, abuse, and dependence on gabapentin and should therefore be treated with caution. The risk of improper use, abuse, or dependence should be carefully assessed before prescribing gabapentin.

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

Post-marketing reports have included cases of abuse and dependence. Patients should be carefully monitored for a history of drug abuse and for possible signs of gabapentin abuse, such as attempts to obtain the drug, demands for dose increases, or development of tolerance.

Dose reduction, discontinuation, or substitution with another (alternative) agent should be performed gradually over at least one week. Abrupt discontinuation of antiepileptic drugs in patients with epilepsy may provoke status epilepticus.

Caution is recommended when treating patients with a history of psychotic disorders.

Alcohol and narcotic use may potentiate CNS-related adverse effects such as confusion and ataxia.

Withdrawal symptoms

Withdrawal symptoms have been observed after discontinuation of both short- and long-term gabapentin treatment. Withdrawal symptoms may occur soon after treatment cessation, usually within 48 hours. The most commonly reported symptoms include anxiety, insomnia, nausea, pain, sweating, tremor, headache, depression, abnormal sensations, 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 beginning of treatment. If gabapentin needs to be discontinued, 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 occur when semi-quantitative determination of urinary total protein is performed using rapid test strips. Therefore, if necessary, additional analyses using other methods (biuret method, turbidimetric method, dye-binding tests) should be performed, or these methods should be used initially.

Excipients

The product contains lactose. Patients with rare hereditary conditions such as lactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding.

Pregnancy.

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.

Risks associated with epilepsy and all anticonvulsant drugs

The risk of congenital malformations in children born to mothers taking anticonvulsant drugs is increased 2-3 times. The most commonly reported malformations include cleft lip, cardiovascular defects, and neural tube defects. Polytherapy with antiepileptic drugs is associated with a higher risk of congenital malformations; therefore, monotherapy should be used whenever possible. Women planning pregnancy and women of childbearing potential should be advised that anticonvulsant therapy should be reviewed in case of planned pregnancy. Anticonvulsant therapy should not be abruptly discontinued, as this may provoke seizures, which could seriously harm both mother and fetus. Developmental delay in children of mothers with epilepsy is rarely observed. It is not possible to determine whether developmental delay in a child is due to genetic, social, maternal disease, or anticonvulsant therapy.

Risks associated with gabapentin therapy

Gabapentin crosses the placenta. There are insufficient data on the use of gabapentin in pregnant women.

Animal studies indicate reproductive toxicity. The potential risk for humans is unknown.

Therefore, gabapentin should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. It is not possible to determine whether gabapentin use is associated with an increased risk of congenital malformations when administered during pregnancy, as both epilepsy and antiepileptic drug use may contribute to such malformations.

Lactation period

Gabapentin passes into breast milk. Since its effects on breastfed infants are unknown, caution should be exercised when prescribing gabapentin to women during lactation. Therefore, breastfeeding should be discontinued during treatment.

Fertility

No effect on fertility was 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 acts on the CNS and may cause somnolence, dizziness, or other similar symptoms. Even if mild or moderate, these adverse effects may be potentially hazardous for patients driving cars or operating machinery, especially at the beginning of treatment and after dose increases.

Method of administration and dosage.

For oral use.

Gabapentin may be taken with or without food. The capsules should be swallowed whole with an adequate amount of water (e.g., 1 glass of water).

For all indications, the recommended dose titration regimen at the beginning of therapy (described in Table 3) applies to adults and children aged 12 years and older.

Table 3

Initial titration schedule
Day 1 300 mg once daily	Day 2 300 mg twice daily	Day 3 300 mg three times daily

Dosing instructions for children under 12 years of age are provided in the section below.

Discontinuation of gabapentin therapy

Clinical data indicate that if gabapentin treatment needs to be discontinued, it should be done gradually over at least 1 week, regardless of the indication.

Epilepsy

Epilepsy usually requires long-term therapy. Doses are determined by the physician according to individual tolerance and treatment efficacy.

Adults and children aged 12 years and older

The effective dose range is 900 to 3600 mg per day.

Treatment can be initiated with dose titration as shown in Table 3, or 300 mg can be administered three times daily starting on day 1. Subsequently, based on individual patient response and drug tolerance, the dose may be increased by 300 mg per day every 2–3 days up to the maximum dose of 3600 mg per day.

For some patients, slower titration of gabapentin dose may be appropriate. The minimum time to reach a dose of 1800 mg per day is 1 week, to reach 2400 mg per day is 2 weeks, and to reach 3600 mg per day is 3 weeks. Data are available showing that doses up to 4800 mg per day were well tolerated in long-term open-label clinical studies. The daily dose should be divided into three administrations. The maximum interval between doses should not exceed 12 hours to prevent seizures.

Children aged 6 years and older

The initial dose should be 10 to 15 mg/kg/day, with effective dose achieved by upward titration over approximately 3 days. The effective dose of gabapentin in children aged 6 years and older is 25–35 mg/kg/day. Data indicate that a dose of 50 mg/kg body weight per day was well tolerated in long-term studies. The total daily dose should be divided into three separate doses, and the maximum interval between doses should not exceed 12 hours.

There is no need to monitor plasma concentrations of the drug. Gabapentin may subsequently be used in combination with other antiepileptic drugs regardless of changes in plasma gabapentin concentrations or serum concentrations of other antiepileptic drugs.

Peripheral neuropathic pain

Adults

Treatment may be initiated with dose titration as specified in Table 3. Alternatively, the initial dose may be 900 mg per day, divided into three separate doses. Subsequently, based on individual patient response and tolerability, the dose may be increased by 300 mg per day every 2–3 days up to the maximum dose of 3600 mg per day. Some patients may require slower dose escalation of gabapentin. The minimum time to reach a dose of 1800 mg per day is 1 week, to reach 2400 mg per day is 2 weeks, and to reach 3600 mg per day is 3 weeks.

For the treatment of peripheral neuropathic pain, particularly painful diabetic neuropathy and postherpetic neuralgia, efficacy and safety have not been studied beyond 5 months of treatment. If a patient requires treatment with gabapentin for more than 5 months for peripheral neuropathic pain, the physician should evaluate the patient's clinical status and determine the need for continued therapy.

Instructions applicable to all indications

For patients with poor general health, low body weight, or who have undergone organ transplantation, the dose should be titrated more slowly, using either a lower-dose formulation or by increasing the intervals between dose increments.

Elderly patients (age over 65 years)

Dose adjustment may be necessary for elderly patients due to age-related decline in renal function (see Table 4).

Somnolence, peripheral edema, and asthenia may occur more frequently in elderly patients.

Renal impairment

Gabapentin dosage must be adjusted in patients with impaired renal function (see Table 4), as well as in patients undergoing hemodialysis.

Table 4

Gabapentin dosing in adults according to renal function

Creatinine clearance (ml/min)	Total daily dose 1) (mg/day)
≥80	900-3600
50-79	600-1800
30-49	300-900
15-29	-600
<153)	-300

1. Divide the total daily dose into 3 doses. Reduced dosage is recommended for patients with renal impairment (creatinine clearance < 79 mL/min).
2. Administer 300 mg once daily.
3. For patients with creatinine clearance < 15 mL/min, the daily dose should be reduced proportionally to creatinine clearance (e.g., patients with creatinine clearance of 7.5 mL/min should receive half the daily dose administered to patients with creatinine clearance of 15 mL/min).

Use in patients undergoing hemodialysis

For anuric patients undergoing hemodialysis who have never previously received gabapentin, a loading dose of 300 to 400 mg is recommended, followed by 200–300 mg of gabapentin after each 4-hour hemodialysis session. Gabapentin should not be administered on days when dialysis is not performed. For patients with impaired renal function undergoing hemodialysis, the maintenance dose of gabapentin should be determined according to the dosing recommendations provided in Table 4. In addition to the maintenance dose, administration of 200–300 mg of the drug after each 4-hour hemodialysis session is recommended.

Pediatric use

Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with or without secondary generalization in children aged 6 years and older. Gabapentin is indicated as monotherapy in the treatment of partial seizures with or without secondary generalization in children aged 12 years and older.

Overdose

Life-threatening acute toxicity has not been observed following gabapentin overdoses up to 49 g. Symptoms of overdose include intensification of adverse effects (dizziness, ataxia, diplopia, blurred speech, dysarthria, somnolence, lethargy, apathy, mild diarrhea).

All patients recovered completely after treatment. Reduced absorption of gabapentin at higher doses may limit drug absorption in overdose situations, thereby minimizing overdose-induced toxicity.

Gabapentin overdose, particularly when combined with other CNS depressants, may result in coma.

Treatment: Symptomatic therapy. Gabapentin may be removed from the bloodstream by hemodialysis. However, experience indicates that this is generally not necessary. Nevertheless, hemodialysis may be effective in patients with severe renal impairment.

In animal studies, no lethal dose was established following oral administration of gabapentin at doses up to 8 g/kg. Signs of acute toxicity observed in animals included ataxia, labored breathing, ptosis, decreased activity, or agitation.

Adverse reactions.

The adverse effects observed in clinical trials for the treatment of epilepsy (the drug was used both as monotherapy and in combination therapy) and neuropathic pain are presented in the table below: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000). Adverse effects reported with varying frequencies across different studies are listed under the category corresponding to the highest observed frequency. Additional adverse events identified from post-marketing surveillance are included in the "unknown" category (frequency cannot be estimated based on available data) and are indicated in italics.

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

Table 5

Adverse reactions

System organ class, frequency	Adverse reactions
Infections and infestations
very common	viral infection
common	pneumonia, respiratory infection, urinary tract infection, otitis media
Blood and lymphatic system disorders
common	leukopenia
frequency unknown	thrombocytopenia
Immune system disorders
uncommon	allergic reactions (e.g. urticaria)
frequency unknown	hypersensitivity syndrome (systemic reaction with various manifestations, namely fever, rash, hepatitis, lymphadenopathy, eosinophilia and, sometimes, other signs and symptoms), anaphylaxis (see section "Special warnings and precautions for use")
Metabolism and nutrition disorders
common	anorexia, increased appetite
uncommon	hyperglycemia (most often in patients with diabetes mellitus)
rare	hypoglycemia (most often in patients with diabetes mellitus)
frequency unknown	hyponatremia
Nervous system disorders
very common	drowsiness, dizziness, ataxia
common	convulsions, hyperkinesia, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances such as paresthesia, hypesthesia, incoordination, nystagmus, increased, decreased or absent reflexes
uncommon	hypokinesia, cognitive disturbance
rare	loss of consciousness
frequency unknown	other movement disorders (e.g. choreoathetosis, dyskinesia, dystonia)
Psychiatric disorders
common	hostility, confusion and emotional lability, depression, anxiety, restlessness, abnormal thinking
uncommon	agitation
frequency unknown	hallucinations, drug dependence
Eye disorders
common	vision disorders, such as amblyopia, diplopia
Ear and labyrinth disorders
common	vertigo
frequency unknown	tinnitus
Cardiac disorders
uncommon	palpitations
Vascular disorders
common	arterial hypertension, vasodilation
Respiratory, thoracic and mediastinal disorders
common	dyspnea, bronchitis, pharyngitis, cough, rhinitis
rare	respiratory depression
Gastrointestinal disorders
common	vomiting, nausea, dental abnormalities, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence
uncommon	dysphagia
frequency unknown	pancreatitis
Hepatobiliary disorders
frequency unknown	hepatitis, jaundice
Skin and subcutaneous tissue disorders
common	facial edema, purpura (most often described as bruises occurring after physical injury), rash, pruritus, acne
unknown	Stevens-Johnson syndrome, toxic epidermal necrolysis, angioneurotic edema, erythema multiforme, alopecia, drug rash with eosinophilia and systemic symptoms (see section "Special warnings and precautions for use")
Musculoskeletal and connective tissue disorders
common	arthralgia, myalgia, back pain, twitching
frequency unknown	rhabdomyolysis, myoclonus
Renal and urinary disorders
frequency unknown	acute renal failure, urinary incontinence
Reproductive system and breast disorders
common	impotence
frequency unknown	breast enlargement, gynecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia)
General disorders
very common	fatigue, fever
common	peripheral edema, gait disturbance, asthenia, pain, malaise, influenza-like syndrome
uncommon	generalized edema
frequency unknown	withdrawal reactions*, chest pain; there have been reports of sudden unexplained deaths where a causal relationship with gabapentin treatment has not been established
Investigations
common	decreased white blood cell count, weight gain
uncommon	increased liver function tests (ALT, AST) and bilirubin
frequency unknown	elevated blood creatine phosphokinase levels
Injury, poisoning and procedural complications
common	accidental injuries, fractures, lacerations
uncommon	falls

Cases of acute pancreatitis have been reported during treatment with gabapentin. A causal relationship with gabapentin has not been established.

There have been reports of myopathy with elevated creatinine levels in patients undergoing hemodialysis with end-stage renal disease.

Data indicate that respiratory infections, middle ear infections, bronchitis, and seizures were observed only in children. Additionally, aggressive behavior and hyperkinesis have been frequently reported in children.

*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, sweating, tremor, headache, depression, abnormal feelings, dizziness, and malaise (see section "Special precautions for use"). 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 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").

Shelf life. 5 years.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 30 °C.

Packaging.

100 capsules in bottles; 10 capsules in blisters, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pharmascience Inc./Pharmascience Inc.

Manufacturer's address and place of business.

6111 Royalmount Avenue, 100, Montreal, Quebec H4P 2T4, Canada/

6111 Royalmount Avenue, 100, Montreal, Quebec H4P 2T4, Canada.