GABAPENTINE ZYDUS 300 mg Gél Plq/90

Capsule.

Hard capsule of size "1" of opaque yellow colour in two parts, the body of the capsule bears the marking "300" printed in black ink and the capsule contains a white to off-white powder.

Gabapentin.................................................................................................................................................300 mg

For one capsule.

Excipients:

Epilepsy

GABAPENTINE ZYDUS is indicated in combination in the treatment of partial epilepsies with or without secondary generalisation in adults and children from 6 years of age (see section Pharmacodynamics).

GABAPENTINE ZYDUS is indicated as monotherapy in the treatment of partial epilepsies with or without secondary generalisation in adults and adolescents from 12 years of age.

Treatment of Peripheral Neuropathic Pain

GABAPENTINE ZYDUS is indicated in the treatment of peripheral neuropathic pain such as diabetic neuropathy and postherpetic neuralgia in adults.

Dosage

For all indications, a titration regimen for initiating treatment is described in table 1. It is recommended for adults and adolescents from 12 years of age. Dosage instructions for children under 12 years of age are provided in a separate subsection later in this section.

Table 1
DOSAGE SCHEDULE - INITIAL TITRATION
Day 1	Day 2	Day 3
300 mg once a day	300 mg twice a day	300 mg three times a day

Discontinuation of gabapentin

If gabapentin must be discontinued, it is recommended, according to current clinical practice, to do so gradually over at least one week regardless of the indication.

Epilepsy

Epilepsy generally requires long-term treatment. The dosage is determined individually by the treating physician based on tolerability and efficacy.

Adults and adolescents

In clinical trials, the range of effective doses was between 900 and 3600 mg/day. Treatment may be initiated by dose titration, as described in table 1, or by administration of 300 mg three times daily (TID) on Day 1.

Subsequently, depending on the patient's response and tolerability, the dose may be increased in steps of 300 mg/day every 2-3 days up to a maximum dose of 3600 mg/day. A slower titration of the gabapentin dosage may be appropriate in some patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day it is 2 weeks in total, and to reach 3600 mg/day it is 3 weeks in total. Dosages up to 4800 mg/day were well tolerated in open-label long-term clinical studies. The total daily dose should be divided into three doses, and the maximum interval between doses should not exceed 12 hours in order to avoid recurrence of seizures.

Children from 6 years of age

The initial dose should be between 10 and 15 mg/kg/day, and the effective dose is reached by upward titration over a period of approximately three days. The effective dose of gabapentin in children from 6 years of age is 25 to 35 mg/kg/day. Dosages up to 50 mg/kg/day were well tolerated in one long-term clinical study. The total daily dose must be divided into three doses and the maximum interval between doses must not exceed 12 hours.

It is not necessary to monitor gabapentin plasma concentrations for the purpose of optimising gabapentin treatment. Furthermore, gabapentin may be used in combination with other antiepileptic medicinal products without concern for any possible alteration of gabapentin plasma concentrations or serum concentrations of the other antiepileptic medicinal products.

Peripheral neuropathic pain

Adults

Treatment may be initiated by dose titration, as described in table 1. The initial dose may alternatively be 900 mg/day divided into three equal doses. Subsequently, depending on the patient's response and tolerability, the dose may be increased in steps of 300 mg/day every 2-3 days up to a maximum dose of 3600 mg/day. A slower titration of the gabapentin dosage may be appropriate in some patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day it is 2 weeks in total, and to reach 3600 mg/day it is 3 weeks in total.

In the treatment of peripheral neuropathic pain such as diabetic neuropathy and postherpetic neuralgia, efficacy and safety have not been studied in clinical trials over treatment periods longer than 5 months. If a patient needs to be treated for more than 5 months for peripheral neuropathic pain, the treating physician should reassess the patient's clinical status and determine the need for continued treatment.

Instruction for all indications

In patients in poor general condition, i.e. with low body weight, after organ transplantation, etc., the dose should be titrated more slowly, by using either lower dosages or longer intervals between dose increases.

Elderly patients (over 65 years)

Elderly patients may require dosage adjustment due to age-related decline in renal function (see table 2). Somnolence, peripheral oedema and asthenia may be more frequent in elderly patients.

Renal impairment

Dose adjustment is recommended in patients with impaired renal function (as described in table 2) and/or in patients undergoing haemodialysis. Gabapentin 100 mg capsules may be used to meet dosage recommendations in patients with renal impairment.

Table 2
GABAPENTIN DOSAGE IN ADULTS ACCORDING TO RENAL FUNCTION
Creatinine clearance (mL/min)	Total daily dosea (mg/day)
≥ 80	900-3600
50-79	600-1800
30-49	300-900
15-29	150b-600
< 15c	150b-300

a The total daily dose must be administered in three separate doses. Reduced dosages apply to patients with renal impairment (creatinine clearance < 79 mL/min).

b The daily dose of 150 mg must be administered as 300 mg every other day.

c For patients whose creatinine clearance is < 15 mL/min, the daily dose should be reduced proportionally to creatinine clearance (e.g., patients with a creatinine clearance of 7,5 mL/min should receive half the daily dose received by patients whose creatinine clearance is 15 mL/min).

Use in haemodialysis patients

For anuric haemodialysis patients who have never been treated with gabapentin, it is recommended to start with a loading dose of 300 to 400 mg, then administer 200 to 300 mg of gabapentin after each 4-hour haemodialysis session. On days without dialysis, gabapentin should not be administered.

For haemodialysed renally impaired patients, the maintenance dose of gabapentin should be based on the dosing recommendations in table 2. In addition to the maintenance dose, an supplementary dose of 200 to 300 mg after each haemodialysis session of 4 hours is recommended.

Method of administration

Oral use.

Gabapentin may be administered with or without meals and must be swallowed whole with a sufficient quantity of liquid (for example: a glass of water).

Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

Severe cutaneous adverse reactions (SCAR)

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or have a fatal outcome, have been reported in association with gabapentin treatment. At the time of prescription, patients must be informed of these signs and symptoms and must be closely monitored for skin reactions. If signs and symptoms suggestive of these reactions appear, gabapentin must be stopped immediately and an alternative treatment should be considered (if applicable).

If a patient has developed a severe reaction of the SJS, TEN or DRESS type during gabapentin treatment, gabapentin must under no circumstances be restarted.

Anaphylaxis

Gabapentin may cause anaphylaxis. Signs and symptoms in reported cases included: breathing difficulties, swelling of the lips, throat and tongue, and hypotension requiring emergency treatment. If signs or symptoms of anaphylaxis appear, patients should be instructed to stop treatment and seek immediate care (see section Adverse effects).

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents for several indications. A meta-analysis of randomised, placebo-controlled trials of antiepileptic drugs also showed a slightly increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known. Cases of suicidal ideation and behaviour have been observed in patients treated with gabapentin after marketing (see section Adverse effects).

Patients (and patients' carers) should be advised to seek medical advice if signs of suicidal thoughts and behaviours appear. Patients should be monitored for possible signs of suicidal thoughts and behaviours, and appropriate treatment should be considered. Discontinuation of treatment with gabapentin should be considered in case of suicidal thoughts and behaviours.

Acute pancreatitis

If a patient develops acute pancreatitis during gabapentin treatment, interruption of gabapentin treatment should be considered (see section Adverse effects).

Seizures

Although no data show an increase in seizures with gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus (see section Dosage and administration).

As with other antiepileptic medicinal products, some patients may experience an increase in seizure frequency or the onset of new seizure types with gabapentin.

As with other antiepileptics, attempts to withdraw concomitant antiepileptics in the treatment of refractory patients treated with one or more antiepileptics, with the aim of achieving gabapentin monotherapy, are less likely to succeed.

Gabapentin is not effective against primary generalised seizures such as absences and may worsen these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizures, including absences.

Treatment with gabapentin has been associated with dizziness and somnolence, which may increase the occurrence of accidental injuries (falls). Cases of confusion, loss of consciousness and impairment of mental faculties have also been reported after marketing authorisation. Consequently, patients should be advised to be cautious until they are accustomed to the potential effects of their treatment.

Concomitant use with opioids and other CNS depressants

Patients requiring concomitant treatment with central nervous system (CNS) depressants, including opioids, must be closely monitored for signs of CNS depression, such as somnolence, sedation and respiratory depression. An increase in gabapentin concentrations may be observed in patients receiving concomitant treatment with gabapentin and morphine. The dose of gabapentin should be reduced accordingly in concomitant treatment with CNS depressants, including opioids (see section Interactions).

Caution is required when gabapentin is prescribed concomitantly with opioids because of the risk of CNS depression. In an observational, case-control study in a population of opioid users, concomitant prescription of opioids and gabapentin was associated with an increased risk of opioid-related deaths compared with the use of opioids prescribed alone (adjusted odds ratio [ORa], 1,49 [95% CI; 1,18 to 1,88; p < 0,001]).

Respiratory depression

Gabapentin has been associated with cases of severe respiratory depression. Patients with impaired respiratory function, those with respiratory or neurological disease, those with renal impairment, those taking concomitant CNS depressants and elderly people may be at higher risk of this serious adverse effect. Dose adjustments may be necessary for these patients.

Elderly patients (over 65 years)

No systematic study of gabapentin has been conducted in patients aged 65 years. In a double-blind study conducted in patients with neuropathic pain, somnolence, peripheral oedema and asthenia were observed, with a higher percentage in patients aged 65 years and older than in younger patients.

Beyond these observations, clinical studies in this age group do not indicate an adverse-effect profile different from that observed in younger patients.

Paediatric population

The effects of long-term treatment with gabapentin (for more than 36 weeks) on learning, intelligence and development in children and adolescents have not been sufficiently studied. The benefits of prolonged treatment should therefore be weighed against the potential risks of such treatment.

Misuse, drug abuse and dependence

Gabapentin may cause drug dependence, which can occur at therapeutic doses. Cases of abuse and misuse have been reported. Patients with a history of substance dependence may present an increased risk of misuse, abuse and dependence on gabapentin, which should therefore be used with caution in these patients. Before prescribing gabapentin, the risk of misuse, abuse or dependence in patients must be carefully assessed.

Patients treated with gabapentin should be monitored for the occurrence of symptoms of misuse, abuse or dependence on gabapentin, such as the development of tolerance, dose escalation and drug-seeking behaviour.

Myasthenia

Gabapentin should be used with caution in patients with myasthenia, as cases of exacerbation of myasthenia have been reported after its marketing authorisation.

Withdrawal symptoms

Following discontinuation or dose reduction of short-term or long-term treatment with gabapentin, withdrawal symptoms have been observed (see section Adverse effects). The patient should be informed of this at the start of treatment. The most frequently reported symptoms are: anxiety, insomnia, nausea, pain, hyperhidrosis, tremor, headache, depression, feeling of abnormal state, dizziness and malaise. The occurrence of withdrawal symptoms may indicate drug dependence. If gabapentin must be discontinued or its dose reduced, it is recommended to do so gradually over a minimum period of 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 urinary protein is performed by reactive dipstick. If a positive result is obtained on reactive dipstick examination, it is therefore recommended to verify this result using methods based on a different analytical principle, such as the Biuret method, turbidimetric or dye-binding methods, or to use these alternative methods from the outset.

Cases of respiratory depression, sedation and death associated with the concomitant use of gabapentin and CNS depressants, including opioids, have been reported spontaneously and are also present in the literature. In some of these cases, the authors considered the combination of gabapentin with opioids to be of particular concern in frail patients, elderly people, patients with serious underlying respiratory disease, polymedicated patients and those with substance use disorders.

In a study conducted in healthy volunteers (N = 12), when a 60 mg extended-release morphine capsule was administered 2 hours before a 600 mg gabapentin capsule, the mean AUC of gabapentin was increased by 44% compared with that of gabapentin administered without morphine. Therefore, patients requiring concomitant opioid treatment need to be closely monitored for signs of CNS depression, such as drowsiness, sedation and respiratory depression, and the dose of gabapentin or opioid should be reduced accordingly.

No interaction has been observed between gabapentin and phenobarbital, phenytoin, valproic acid or carbamazepine.

The steady-state pharmacokinetic parameters of gabapentin are similar in healthy subjects and in epileptic patients receiving these antiepileptic agents.

Concomitant administration of gabapentin and oral contraceptives containing norethindrone and/or ethinyl estradiol does not alter the steady-state pharmacokinetic parameters of either product.

Concomitant administration of gabapentin and aluminium- and magnesium-containing antacids may reduce the bioavailability of gabapentin by up to 24 %. It is recommended that gabapentin be taken at least two hours after taking an antacid.

Renal excretion of gabapentin is not modified by probenecid.

The slight decrease in renal excretion of gabapentin observed with concomitant administration of cimetidine is not expected to have any clinical impact.

Pregnancy

Risk related to epilepsy and antiepileptic drugs (AEDs) in general

Women of childbearing potential, particularly those planning a pregnancy or who are pregnant, should be given informed advice regarding the risk to the foetus associated with both seizures and antiepileptic treatment. The need for antiepileptic treatment should be reassessed when a woman plans to become pregnant. In women treated for epilepsy, abrupt discontinuation of antiepileptic treatment should be avoided as it may lead to breakthrough seizures, which could have serious consequences for both mother and child. Monotherapy should be favoured whenever possible, as treatment with several AEDs may be associated with an increased risk of congenital malformations compared with monotherapy, depending on the antiepileptic used.

Risk related to gabapentin

Gabapentin crosses the placental barrier.

Data from an observational study conducted in the Nordic countries involving more than 1 700 pregnancies exposed to gabapentin during the first trimester revealed no increased risk of major congenital malformations in the paediatric population exposed to gabapentin compared with the unexposed paediatric population and the paediatric population exposed to pregabalin, to lamotrigine combined with pregabalin, or to lamotrigine. Likewise, no increased risk of neurodevelopmental disorders was observed in the paediatric population exposed to gabapentin during pregnancy.

In newborns of women exposed to gabapentin, there were limited data suggesting an increased risk of low birth weight and preterm birth but not stillbirth, small size for gestational age, low Apgar score at 5 minutes, or microcephaly.

Studies performed in animals have shown reproductive toxicity (see section Preclinical safety). Gabapentin may be taken during the first trimester of pregnancy if clinically necessary.

Cases of neonatal withdrawal syndrome have been reported in newborns exposed in utero to gabapentin. Concomitant exposure to gabapentin and opioids during pregnancy may increase the risk of neonatal withdrawal syndrome. Newborns should be closely monitored.

Breast-feeding

Gabapentin passes into breast milk. As the effect on the breastfed infant is not known, gabapentin should be administered with caution to breastfeeding mothers. Gabapentin should only be used in breastfeeding mothers if the benefits clearly outweigh the risks.

Fertility

There is no effect on fertility in animal studies (see section Preclinical safety).

Gabapentin may have a minor or moderate influence on the ability to drive vehicles and use machines. Gabapentin acts on the central nervous system and may cause somnolence, dizziness or other related symptoms.

Even if they were only of mild or moderate intensity, these adverse effects could be potentially dangerous in patients who drive or use machines. This is particularly the case at the beginning of treatment and after each dose increase.

The adverse reactions observed during clinical studies conducted in epilepsy (as adjunctive therapy and as monotherapy) and in neuropathic pain have been grouped into a single list below, by system organ class and by frequency: 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). When an adverse reaction was observed at different frequencies in clinical studies, the highest frequency was assigned to it.

Adverse reactions reported after marketing (in italics in the list below) are listed with an unknown frequency (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class	Adverse effects
Infections and infestations
Very common	Viral infection.
Common	Pneumonia, respiratory infection, urinary tract infection, infection, otitis media.
Blood and lymphatic system disorders
Common	Leukopenia.
Frequency not known	Thrombocytopenia.
Immune system disorders
Uncommon	Allergic reactions (for example urticaria).
Frequency not known	Hypersensitivity syndrome (systemic reaction with varied presentation which may include fever, skin rash, hepatitis, lymphadenopathy, eosinophilia, and sometimes other signs and symptoms), anaphylaxis (see section Warnings and precautions).
Metabolism and nutrition disorders
Common	Anorexia, increased appetite.
Uncommon	Hyperglycaemia (more frequently observed in diabetic patients).
Rare	Hypoglycaemia (more frequently observed in diabetic patients).
Frequency not known	Hyponatremia.
Psychiatric disorders
Common	Aggression, confusion and emotional lability, depression, anxiety, nervousness, thought disorder.
Uncommon	Agitation.
Frequency not known	Suicidal ideation, hallucinations, drug dependence.
Nervous system disorders
Very common	Somnolence, dizziness, ataxia.
Common	Convulsions, hyperkinesia, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances such as paraesthesia, hypoaesthesia, coordination disorders, nystagmus, increased, decreased or absent reflexes.
Uncommon	Hypokinesia, impairment of mental faculties.
Rare	Loss of consciousness.
Frequency not known	Other abnormal movements (for example: choreoathetosis, dyskinesia, dystonia).
Eye disorders
Common	Visual disturbances such as amblyopia, diplopia.
Ear and labyrinth disorders
Common	Vertigo.
Frequency not known	Tinnitus.
Cardiac disorders
Uncommon	Palpitations.
Vascular disorders
Common	Arterial hypertension, vasodilation.
Respiratory, thoracic and mediastinal disorders
Common	Dyspnoea, bronchitis, pharyngitis, cough, rhinitis.
Rare	Respiratory depression
Gastrointestinal disorders
Common	Vomiting, nausea, dental abnormalities, gingivitis, diarrhoea, abdominal pain, dyspepsia, constipation, dryness of the mouth or throat, flatulence.
Uncommon	Dysphagia
Frequency not known	Pancreatitis.
Hepatobiliary disorders
Frequency not known	Hepatitis, jaundice.
Skin and subcutaneous tissue disorders
Common	facial oedema, purpura most often described as bruises resulting from physical trauma, rash, pruritus, acne.
Frequency not known	Stevens-Johnson syndrome, toxic epidermal necrolysis, Quincke's oedema, erythema multiforme, alopecia, rash with eosinophilia and systemic symptoms (see section Warnings and precautions).
Musculoskeletal and systemic disorders
Common	Arthralgia, myalgia, dorsalgia, involuntary muscle contractions.
Frequency not known	Rhabdomyolysis, myoclonus, exacerbation of myasthenia gravis.
Renal and urinary disorders
Frequency not known	Acute renal failure, urinary incontinence.
Disorders of the reproductive system and breast
Common	Impotence.
Frequency not known	Breast hypertrophy, gynecomastia, sexual disorders (including changes in libido, ejaculation disorders and anorgasmia).
General disorders and administration site conditions
Very common	Fatigue, fever.
Common	peripheral oedema, gait disturbances, asthenia, pain, malaise, influenza-like syndrome.
Uncommon	generalised oedema.
Frequency not known	Withdrawal syndrome*, chest pain. Unexplained sudden deaths have been reported, but no causal relationship with gabapentin treatment has been established.
Investigations
Common	Decrease in white blood cell count, weight gain.
Uncommon	Elevations of liver enzymes (SGOT (AST), SGPT (ALT)) and of bilirubin.
Frequency not known	Elevation of creatine phosphokinase in the blood.
Injury, poisoning and procedural complications
Common	Accidental injuries, fracture, abrasion.
Uncommon	Fall.

* After discontinuation or dose reduction of short- or long-term treatment with gabapentin, withdrawal symptoms have been observed. Withdrawal symptoms may appear shortly after discontinuation or dose reduction of the treatment, generally within 48 hours (see section Warnings and precautions).

Cases of acute pancreatitis have been reported during treatment with gabapentin. The causality with gabapentin is not elucidated (see section Warnings and precautions).

In patients undergoing haemodialysis due to end-stage renal failure, cases of myopathy with elevation of creatine kinase have been reported.

Respiratory infections, otitis media, convulsions and bronchitis have been reported only in clinical studies conducted in children. In clinical studies carried out in children, aggressive behaviour and hyperkinesia have also been frequently reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.

No acute toxicity life-threatening has been observed in cases of gabapentin overdose up to 49 g. Symptoms of overdose include: dizziness, double vision, speech disorders, drowsiness, loss of consciousness, lethargy and mild diarrhoea. All patients recovered completely with supportive treatment. At higher doses, reducing the absorption of gabapentin during overdose may limit drug absorption and thereby minimise overdose toxicity.

An overdose of gabapentin, particularly in combination with other central nervous system depressant medicines, may cause coma.

Gabapentin can be removed by haemodialysis, but experience shows that this method is usually not necessary. However, in patients with severe renal impairment, haemodialysis may be indicated.

No oral lethal dose of gabapentin has been identified in mice and rats given doses up to 8000 mg/kg. Signs of acute toxicity in animals were: ataxia, respiratory difficulty, ptosis, hypoactivity or excitation.

Pharmacotherapeutic class: Other antiepileptics, ATC code: N02BF01.

Mechanism of action

Gabapentin readily penetrates the brain and prevents convulsions in a number of animal models of epilepsy. Gabapentin has no affinity for GABAA and GABAB receptors and does not alter GABA metabolism. It does not bind to other brain neurotransmitter receptors and does not interact with sodium channels. Gabapentin binds with high affinity to the α2δ (alpha-2-delta) subunit of voltage-dependent calcium channels, and it is assumed that binding to the α2δ subunit may be involved in the anticonvulsant effects of gabapentin in animals. Broad-panel screening does not suggest any other drug target than the α2δ subunit.

Evidence from several pre-clinical models indicates that the pharmacological activity of gabapentin may be mediated by binding to α2δ through a reduction in the release of excitatory neurotransmitters in certain regions of the central nervous system. This activity may be what underlies the anticonvulsant activity of gabapentin. The relevance of these actions of gabapentin to its anticonvulsant effects remains to be established in humans.

Gabapentin has also proven effective in several pre-clinical animal models of pain. In animal models, it is assumed that the specific binding of gabapentin to the α2δ subunit results in several different actions that may be responsible for this analgesic activity. The analgesic effects of gabapentin probably occur in the spinal cord, as well as in higher centres of the brain, through interactions with descending pain-inhibitory pathways. The relevance of these pre-clinical properties to the clinical action in humans is unknown.

Clinical efficacy and safety

A clinical study in the treatment of partial epilepsies as an adjunct to other treatments, in children aged 3 to 12 years, showed a numerical, but not statistically significant, difference in responder rates of 50% in favour of the gabapentin group compared with placebo. Additional post-hoc analyses of responder rates by age did not reveal a statistically significant effect of age, either as a continuous or a dichotomous variable (age bands of 3 to 5 years and 6 to 12 years).

The data from this additional post-hoc analysis are summarised in the table below:

Response (≥ 50 % Improvement) by Treatment and Age of the ITTM* Population
Age Class	Placebo	Gabapentin	P-value
< 6 years	4/21 (19,0%)	4/17 (23,5%)	0,7362
6 to 12 years	17/99 (17,2%)	20/96 (20,8%)	0,5144

*The modified intent-to-treat population was defined as all patients randomised to study drug who also had evaluable seizure records over 28 days both at pre-treatment and during double-blind treatment.

Absorption

After oral administration, plasma concentrations of gabapentin peak within 2 to 3 hours. The bioavailability (fraction of dose absorbed) of gabapentin tends to decrease with increasing dose. The absolute bioavailability of a 300 mg capsule is approximately 60%. Food, including a high-fat meal, has no clinically significant effect on the pharmacokinetic parameters of gabapentin.

The pharmacokinetic parameters of gabapentin are not affected by repeated administration. Although plasma concentrations of gabapentin have generally ranged between 2 µg/mL and 20 µg/mL in clinical studies, such concentrations have not been predictive of safety or efficacy. The pharmacokinetic parameters are presented in table 3.

Table 3
SUMMARY OF MEAN PHARMACOKINETIC PARAMETERS (CV, %) AT STEADY STATE OF GABAPENTIN AFTER ADMINISTRATION EVERY EIGHT HOURS
Parameters Pharmacokinetics	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)
t½ (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 plasma concentration at steady state

Tmax = Time to Cmax

t½ = Elimination half-life

AUC (0-8) = Area under the plasma concentration curve at steady state between 0 and 8 hours after dosing

Ae% = Percentage of the dose excreted unchanged in urine between 0 and 8 h after dosing

ND = Not available

Distribution

Gabapentin does not bind to plasma proteins and its volume of distribution is 57,7 litres. In epileptic patients, gabapentin concentrations in cerebrospinal fluid (CSF) were approximately 20% of the corresponding plasma concentrations at steady state. Gabapentin passes into the breast milk of nursing women.

Biotransformation

No data show that gabapentin is metabolised in humans. Gabapentin exerts no inducing effect on the mixed-function oxidases responsible for drug metabolism.

Elimination

Gabapentin is eliminated unchanged only via the renal route. The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours.

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

Gabapentin can be removed from plasma by haemodialysis. Dose adjustment is recommended in renally impaired patients and in haemodialysis patients (see section Dosage and administration).

The pharmacokinetic parameters of gabapentin in children were determined in 50 healthy subjects aged 1 month to 12 years. In general, plasma gabapentin concentrations in children aged > 5 years are similar to those in adults, expressed in mg/kg.

In a pharmacokinetic study conducted in 24 healthy children aged 1 month to 48 months, a reduction of approximately 30% in the area under the plasma concentration curve (AUC), a reduction in Cmax and an increase in body-surface-area-weighted creatinine clearance were observed in comparison with available data in children aged over 5 years.

Linearity/non-linearity

The bioavailability (fraction of dose absorbed) of gabapentin decreases with increasing dose, which confers non-linearity on the pharmacokinetic parameters, including bioavailability parameters (F), e.g. Ae%, CL/F, Vd/F. The elimination pharmacokinetics (pharmacokinetic parameters not including F parameters such as CLr and t½) is better described by linear pharmacokinetics. Steady-state plasma gabapentin concentrations are predictable from single-dose data.

Carcinogenesis

Gabapentin was administered in the diet to mice at doses of 200, 600 and 2000 mg/kg/day and to rats at doses of 250, 1000 and 2000 mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar tumours was found only in male rats at the highest dose. The maximum plasma concentrations reached in rats treated with 2000 mg/kg/day are 10 times higher than the plasma concentrations reached in subjects treated with 3600 mg/day. The pancreatic acinar tumours in male rats are low-grade malignant tumours; they did not affect survival, did not metastasise or invade adjacent tissues, and were similar to those observed in concurrent controls. The relevance of these pancreatic acinar tumours in male rats to the carcinogenic risk in humans is not clear.

Mutagenesis

Gabapentin has not shown genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. Gabapentin did not induce structural chromosomal aberrations in mammalian cells in vitro or in vivo and did not induce micronucleus formation in the bone marrow of hamsters.

Impairment of fertility

No adverse effects on fertility or reproduction were observed in rats treated with doses up to 2000 mg/kg (approximately five times the maximum human daily dose expressed in mg/m2 of body surface area).

Teratogenesis

Gabapentin did not increase the incidence of malformations, compared with controls, in the offspring of mice, rats or rabbits treated at doses up to 50, 30 and 25 times the human daily dose of 3600 mg respectively (four, five or eight times the human daily dose expressed in mg/m2).

Gabapentin induced delayed ossification of the skull, vertebrae, forelimbs and hindlimbs in rodents, indicating delayed fetal growth. These effects occurred in pregnant mice given oral doses of 1000 or 3000 mg/kg/day during organogenesis and in female rats given 2000 mg/kg before and during mating and throughout gestation. These doses correspond to approximately 1 to 5 times the human dose of 3600 mg expressed in mg/m2.

No effect was observed in pregnant mice receiving 500 mg/kg/day (approximately 1/2 of the human daily dose expressed in mg/m2).

An increased incidence of hydroureter and/or hydronephrosis was observed in rats treated with 2000 mg/kg/day in a general fertility and reproduction study, with 1500 mg/kg/day in a teratology study and with 500, 1000 and 2000 mg/kg/day in a perinatal and postnatal study. The significance of these observations is not known, but they were associated with delayed development. These doses also represent approximately 1 to 5 times the human dose of 3600 mg expressed in mg/m2.

In a teratology study in rabbits, an increased incidence of post-implantation fetal loss was observed in pregnant female rabbits receiving 60, 300 and 1500 mg/kg/day during organogenesis. These doses represent approximately 0,3 to 8 times the human daily dose of 3600 mg expressed in mg/m2. Safety margins are insufficient to exclude the risk of these effects in humans.

3 years.

To be stored at a temperature not exceeding 30°C.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400930149263 (Plq/90).

Price:

18,15 euros (Plq/90).

Social security reimbursement at 65% based on the TFR: 18.15 euros (Plq/90) in the indications:

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree

Collection.