Neurontin 100mg. 300mg. 400mg. 600mg. 800mg Tablets, capsules

NEURONTIN is indicated in controlling both simple and complex partial seizures with or without secondary generalised tonic-clonic seizures in adults and children over 12 years of age. NEURONTIN is indicated as adjunctive therapy with standard anti-epileptic medicines in patients who have not achieved adequate seizure control with these medicines used alone or in combination.

General
When in the judgment of the medical practitioner there is a need for dose reduction, discontinuation, or substitution of alternative anticonvulsant medicine, this should be done gradually over a minimum of one week. It is unnecessary to monitor NEURONTIN plasma concentrations to optimise NEURONTIN therapy. NEURONTIN may be used in combination with phenobarbital, phenytoin, valproic acid and carbamazepine without concern for alteration of the plasma concentrations or serum concentrations of NEURONTIN or the other anti-epileptic medicines.

Posology
Epilepsy
Adults and children over 12 years of age
Usual effective dose: 900 u2013 1 800 mg/day in three divided doses with not more than 12 hours between doses. Since titration to an effective dose can progress rapidly, this may be accomplished in as few as three days using one of the following approaches: In clinical trials, the effective dosing range was 900 mg to 1 000 mg/day. Therapy should be initiated by titrating the dose as described in Table 1. Thereafter, the dose can be increased in three equally divided doses up to a maximum dose of 1 800 mg/day.

Table 1
Dosing chart u2013 Initial titration
Dose
Day 1
Day 2
Day 3
900 mg
300 mg once a day
300 mg two times a day
300 mg three times a day

Special populations
Elderly
Elderly patients should be carefully monitored for adverse events. Elderly patients may require dosage adjustment because of declining renal function with age. Adjust according to creatinine clearance as described in Table 2.

Compromised renal function
The elimination of NEURONTIN is decreased in patients with impaired renal function. This patient population has not been fully examined but the following guidelines are based on information derived from single doses in non-epileptic patients. For patients with compromised renal function or those undergoing haemodialysis the following maintenance dosage is recommended.

Table 2
Renal function
Creatinine clearance (mL/min)
Total daily dose (mg/day)
Dose regiment (mg)
> 60
1 200
400 three times a day
> 30 u2013 60
600
300 twice a day
15 u2013 30
300
300 once a day
< 15
150
300 every other day
Haemodialysis
- 200 u2013 300
a Loading dose of 300 to 400 mg
b Maintenance dose of 200 to 300 mg NEURONTIN following each 4 hours of haemodialysis

Paediatric population
Epilepsy
Safety and effectiveness in children under 12 years of age have not been established.

Method of administration
For oral use. NEURONTIN may be given with or without food.

• Hypersensitivity to gabapentin or to any of the excipients of NEURONTIN (listed in section 6.1).
• Safety and efficacy have not been established in children 12 years of age or younger.
• Severe impaired renal function.

General
Although there is no convincing evidence of rebound seizures with NEURONTIN, abrupt withdrawal of NEURONTIN in epileptic patients may precipitate status epilepticus. NEURONTIN is not generally considered effective in the treatment of absence seizures. Do not allow more than 12 hours between NEURONTIN doses to prevent breakthrough convulsions. NEURONTIN treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall). There have also been post-marketing reports of confusion, loss of consciousness and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of NEURONTIN.

Concomitant use with opioids and other CNS depressants
Patients who require concomitant treatment with central nervous system (CNS) depressants, including opioids, should be carefully observed for signs of CNS depression, such as somnolence, sedation and respiratory depression. Patients who use NEURONTIN and morphine concomitantly may experience increases in NEURONTIN concentrations. The dose of NEURONTIN, or concomitant treatment with CNS depressants including opioids, should be reduced appropriately (see section 4.5).

Caution is advised when prescribing NEURONTIN concomitantly with opioids due to risk of CNS depression.
In a population-based, observational, nested case-control study of opioid users, co-prescription of opioids and NEURONTIN was associated with an increased risk for opioid-related death compared to opioid prescription use alone (adjusted odds ratio [aOR], 1,49 [95 % CI, 1,18 to 1,88, p<0,001]).

Respiratory depression
NEURONTIN has been associated with severe respiratory depression. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly might be at higher risk of experiencing this severe adverse reaction. Dose adjustments might be necessary in these patients.

Drug rash with eosinophilia and systemic symptoms (DRESS)
Severe, life-threatening, systemic hypersensitivity reactions such as drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking anti-epileptic medicines including NEURONTIN. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. NEURONTIN should be discontinued if an alternative aetiology for the signs or symptoms cannot be established.

Anaphylaxis
NEURONTIN can cause anaphylaxis. Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue NEURONTIN and seek immediate medical care should they experience signs or symptoms of anaphylaxis (see section 4.8).

Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with NEURONTIN in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicines has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for NEURONTIN. Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients and caregivers should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Misuse, abuse potential or dependence
Cases of misuse, abuse and dependence have been reported. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of NEURONTIN misuse, abuse or dependence (development of tolerance, dose escalation, intentional overdose, drug-seeking behaviour have been reported).

Lactose intolerance
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

There are spontaneous and literature case reports of respiratory depression, sedation and death associated with NEURONTIN when co-administered with CNS depressants, including opioids. In some of these reports, the authors considered the combination of NEURONTIN with opioids to be a particular concern in frail patients, in the elderly, in patients with serious underlying respiratory disease, with polypharmacy, and in those with substance abuse disorders (see section 4.4).

Morphine
In a study involving healthy volunteers (n=12), when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg NEURONTIN capsule, the mean NEURONTIN AUC increased by 44 % compared to NEURONTIN administered without morphine. The clinical significance of such changes has not been defined. Morphine pharmacokinetic parameter values were not affected by administration of NEURONTIN 2 hours after morphine. The observed opioid-mediated side effects associated with morphine plus NEURONTIN in the volunteers did not differ significantly from morphine plus placebo. The magnitude of interaction at other doses is not known (see section 4.4).

There is no interaction between NEURONTIN and phenobarbital, phenytoin, valproic acid or carbamazepine. NEURONTIN steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving anti-epileptic medicines. Co-administration of NEURONTIN with oral contraceptives containing norethindrone and/or ethinyl estradiol does not influence the steady-state pharmacokinetics of either component. Co-administration of NEURONTIN with a magnesium-and aluminium-containing antacid reduces NEURONTIN bioavailability by approximately 20 %. It is recommended that NEURONTIN be taken about two hours before or after antacid administration. Renal excretion of NEURONTIN is unaltered by probenecid. A slight decrease in renal excretion of NEURONTIN observed when it is co-administered with cimetidine is not expected to be of clinical importance.

Laboratory tests
False positive tests for proteinuria may occur with the Ames Multistix-SG dipstick test when NEURONTIN is added to other anticonvulsant medicines. To determine urinary protein, the more specific sulfosalicylic acid precipitation procedure is recommended.

Pregnancy
Risk related to epilepsy and anti-epileptic medicines in general
Specialist advice regarding the potential risk to a foetus caused by both seizures and anti-epileptic treatment should be given to women of childbearing potential, and especially to women planning for pregnancy and women who are pregnant. The need for anti-epileptic treatment should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, no sudden discontinuation of anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child. Monotherapy should be preferred whenever possible because therapy with multiple anti-epileptic medicines could be associated with a higher risk of congenital malformations than monotherapy, depending on the anti-epileptics used.

Risk related to NEURONTIN
NEURONTIN crosses the human placenta. Data from a Nordic observational study of more than 1 700 pregnancies exposed to NEURONTIN in the first trimester showed no higher risk of major congenital malformations among the children exposed to NEURONTIN compared to the unexposed children. Likewise, no increased risk of neurodevelopmental disorders was observed in children exposed to NEURONTIN during pregnancy. There was limited evidence of a higher risk of low birth weight and preterm birth but not of stillbirth, small for gestational age, low Apgar score at 5 minutes and microcephaly in newborns of women exposed to NEURONTIN. Studies in animals have shown reproductive toxicity. NEURONTIN can be used during the first trimester of pregnancy if clinically needed. Neonatal withdrawal syndrome has been reported in newborns exposed in utero to gabapentin. Co-exposure to gabapentin and opioids during pregnancy may increase the risk of neonatal withdrawal syndrome. Newborns should be monitored carefully.

Breastfeeding
NEURONTIN is excreted in human milk. Because the effect on the nursing infant is unknown, caution should be exercised when gabapentin is administered to a breastfeeding mother.

Fertility
There is no effect on fertility in animal studies.

NEURONTIN frequently causes dizziness and somnolence. Therefore, patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicine affects their ability to perform these activities.

Summary of the safety profile
Epilepsy
The following side effects have been reported: The most frequent clinical adverse events occurring in all clinical studies were somnolence, dizziness, ataxia, headache, nystagmus, tremor, fatigue, diplopia, nausea and/or vomiting and rhinitis.

Tabulated summary of adverse reactions
From data drawn from placebo-controlled studies, adverse events are listed in descending order of frequency both by bodily system and by associated adverse events:

Very common u2265 1/10; common u2265 1/100 to < 1/10; uncommon u2265 1/1 000 to < 1/100; rare u2265 1/10 000 to < 1/1 000; very rare < 1/10 000.

MedDRA System Organ Class
Frequency
Undesirable effect

Infections and infestations
Common
Viral infection, respiratory infection

Blood and lymphatic system disorders
Common
Leukopenia

Metabolism and nutrition disorders
Common
Increased appetite

Psychiatric disorders
Common
Confusion, depression, emotional lability, nervousness, abnormal thinking

Nervous system disorders
Very common
Ataxia, dizziness, somnolence
Common
Amnesia, abnormal coordination, dysarthria, insomnia, headache, nystagmus, tremor

Eye disorders
Common
Amblyopia, diplopia

Vascular disorders
Common
Vasodilation

Respiratory, thoracic and mediastinal disorders
Common
Dyspnoea, cough, pharyngitis, rhinitis
Rare
Respiratory depression

Gastrointestinal disorders
Common
Abdominal pain, constipation, dental abnormalities, diarrhoea, dyspepsia, dry mouth or throat, nausea, vomiting

Skin and subcutaneous tissue disorders
Common
Acne, pruritus, rash

Musculoskeletal and connective tissue disorders
Common
Back pain, myalgia, twitching

Reproductive system and breast disorders
Common
Impotence

General disorders and administration site conditions
Very common
Fatigue
Common
Fever, peripheral oedema

Investigations
Common
Decreased WBC (white blood cell count), weight increase

Injury, poisoning and procedural complications
Common
Abrasion, fracture

Post-marketing experience
The following cases have been reported:

MedDRA System Organ Class
Undesirable effect

Blood and lymphatic system disorders
Thrombocytopenia

Immune system disorders
Allergic reaction including urticaria, anaphylaxis, anaphylactoid reaction, hypersensitivity including systemic reactions

Metabolism and nutrition disorders
Hyperglycaemia and hypoglycaemia (most often observed in patients with diabetes), hyponatraemia

Psychiatric disorders
Hallucinations, agitation

Nervous system disorders
Movement disorders such as choreoathetosis, dyskinesia, and dystonia, spastic torticollis and myoclonus, loss of consciousness

Ear and labyrinth disorders
Tinnitus

Cardiac disorders
Palpitation, chest pain

Gastrointestinal disorders
Pancreatitis

Hepatobiliary disorders
Hepatitis, jaundice

Skin and subcutaneous tissue disorders
Alopecia, angioedema, erythema multiforme, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal and connective tissue disorders
Rhabdomyolysis

Renal and urinary disorders
Acute kidney failure, urinary incontinence

Reproductive system and breast disorders
Breast hypertrophy, gynaecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia)

General disorders and administration site conditions
Adverse events following the abrupt discontinuation of NEURONTIN have also been reported. The most frequently reported events were anxiety, insomnia, nausea, sweating, depression, headache, pain, tremor, agitation, panic attacks, diarrhoea, dizziness, tachycardia, confusion and generalised oedema. Sudden unexplained deaths have been reported where a causal relationship to treatment with NEURONTIN has not been established.

Investigations
Elevated liver function tests (LFTs), increased blood creatine phosphokinase

Injury, poisoning and procedural complications
Fall

Some of these could represent seizure-related deaths in which the seizure was not observed e.g. at night. This represents an incidence of 0,0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving NEURONTIN (ranging from 0,0005 for the general population of epileptics, to 0,003 for a clinical trial population similar to that in the NEURONTIN program, to 0,005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the NEURONTIN cohort and the accuracy of the estimates provided.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

No specific information is available on the treatment of overdose with NEURONTIN, although haemodialysis has been shown to be effective in eliminating NEURONTIN. Treatment is symptomatic and supportive, consistent with established medical care. Overdoses of NEURONTIN up to 49 g ingested at one time have been reported in four people, all of whom recovered fully. Symptoms of overdose included dizziness, double vision, slurred speech, drowsiness, loss of consciousness, lethargy and mild diarrhoea. An oral lethal dose of NEURONTIN was not identified in mice and rats given doses as high as 8 000 mg/kg. Signs of acute toxicity in animals included ataxia, laboured breathing, ptosis, hypoactivity or excitation. Reduced absorption of NEURONTIN at higher doses may limit medicine absorption and hence minimise toxicity at the time of overdosing. In patients with renal impairment haemodialysis may be indicated.