NUPENTIN

Epilepsy

NEURONTIN is indicated in association in the treatment of partial epilepsies with or without secondary generalization in adults and children from 6 years (see section 5.1).

NEURONTIN is indicated as monotherapy in the treatment of partial epilepsies with or without secondary generalization in adults and adolescents from 12 years.

Treatment of Peripheral Neuropathic Pain

NEURONTIN is indicated in the treatment of peripheral neuropathic pain such as diabetic neuropathy and post-herpetic neuralgia in adults.

Cases of respiratory depression, sedation and death associated with the concomitant use of gabapentin and CNS depressants, including opioids, have been reported spontaneously and also exist in the literature.

In some of these cases, authors considered the association of gabapentin with opioids to be particularly concerning in frail patients, in the elderly, in patients with severe underlying respiratory disease, in polymedicated patients and in 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 to gabapentin administered without morphine. Consequently, it is necessary to closely monitor patients requiring concomitant opioid treatment for signs of CNS depression, such as drowsiness, sedation and respiratory depression, and the dose of gabapentin or opioids should be reduced accordingly.

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

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

The concomitant administration of gabapentin and oral contraceptives containing norethindrone and/or ethinylestradiol does not modify the steady-state pharmacokinetic parameters of each of these products.

The concomitant administration of gabapentin and antacids containing aluminium and magnesium can reduce the bioavailability of gabapentin by up to 24 %. It is recommended to take gabapentin at least two hours after taking an antacid.

The renal excretion of gabapentin is not modified by probenecid.

The slight decrease in the renal excretion of gabapentin observed during concomitant administration of cimetidine should not have a clinical impact.

Pregnancy

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

Expert advice regarding the risk to the fetus associated with both seizures and antiepileptic treatment must be given to women of childbearing potential, particularly those planning a pregnancy or who are pregnant. The need for antiepileptic treatment must be re-evaluated when a woman is planning a pregnancy. In women treated for epilepsy, sudden discontinuation of antiepileptic treatment must be avoided as it may lead to breakthrough seizures, which could have serious consequences for both the mother and the child. Monotherapy should be preferred whenever possible, as treatment with multiple AEDs could be associated with an increased risk of congenital malformations compared to 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 on more than 1 700 pregnancies exposed to gabapentin during the first trimester revealed no increased risk of major congenital malformations in the pediatric population exposed to gabapentin compared to the unexposed pediatric population and the pediatric population exposed to pregabalin, lamotrigine associated with pregabalin, or lamotrigine. Similarly, no increased risk of neurodevelopmental disorders was observed in the pediatric population exposed to gabapentin during pregnancy.

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

Studies performed in animals have shown reproductive toxicity (see section 5.3).

Gabapentin can be taken during the first trimester of pregnancy if clinically necessary.

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

Breastfeeding

Gabapentin is excreted in human milk. Given that the effect on the breastfed infant is not known, gabapentin should be administered with caution to a breastfeeding mother. Gabapentin should only be used in a breastfeeding mother if the benefits clearly outweigh the risks.

Fertility

There is no effect on fertility in studies conducted in animals (see section 5.3).

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 can cause drowsiness, dizziness or other related symptoms. Even if they were only of mild or moderate intensity, these side effects could potentially be dangerous in patients who drive or use machines. This is notably the case at the start of treatment and after each dose increase.

The adverse effects observed during clinical studies conducted in epilepsy (in combination and in monotherapy) and in neuropathic pain have been grouped into a single list appearing below, by class and by frequency: very frequent (≥ 1/10), frequent (≥ 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 effect was observed at different frequencies in clinical studies, the highest frequency was attributed to it.

The adverse effects reported after marketing (in italics in the list below) are mentioned with an undetermined frequency (cannot be estimated on the basis of available data).

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

* After stopping or reducing the dose of a short or long-term treatment with gabapentin, withdrawal symptoms have been observed. Withdrawal symptoms may appear shortly after stopping or reducing the dose of the treatment, generally within 48 hours.

Cases of acute pancreatitis have been reported during gabapentin treatments. Causality with gabapentin is not elucidated (see section 4.4).

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

Respiratory infections, middle ear infections, convulsions and bronchitis have only been reported in clinical studies conducted in children. In clinical studies conducted in children, aggressive behaviour and hyperkinesia have also been frequently reported.

Reporting of suspected adverse effects

Reporting suspected adverse effects after medicinal product authorization is important. It allows for continuous monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals report any suspected adverse effect via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/ .