Indications:
Epilepsy:
Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults and children 6 years of age and above.
Gabapentin is indicated as monotherapy in the treatment of partial seizures, with or without secondary generalization in adults and adolescents 12 years of age and above.
Treatment of peripheral neuropathic pain:
Gabapentin is indicated for the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia in adults.
Administration, dosage:
Administration: Gabapentin is taken orally with enough water, regardless of the meal.
Dosage:
In all indications, a titration scheme for the initiation of therapy is described in Table 1, which is recommended for adults and adolescents aged 12 years and above. Dosing instructions for children under 12 years of age are provided under a separate sub-heading later in this section.
Table 1:
| Dosing chart – Initial titration | ||
| Day 1 | Day 2 | Day 3 |
| 300mg once a day | 300mg two times a day | 300mg three times a day |
Discontinuation of gabapentin:
If gabapentin has to be discontinued, it is recommended this should be done gradually over a minimum of 1 week independent of the indication.
Epilepsy:
Epilepsy typically requires long-term therapy. Dosage is determined by the treating physician according to individual tolerance and efficacy.
Adults and adolescents:
In clinical trials, the effective dosing range was 900 to 3600mg/day. Therapy may be initiated by titrating the dose as described in Table 1.
Or administering 300mg three times a day on Day 1. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300mg/day increments every 2-3 days up to a maximum dose of 3600mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800mg/day is one week, to reach 2400mg/day is a total of 2 weeks, and to reach 3600mg/day is a total of 3 weeks.
Dosages up to 4800mg/day have been well tolerated in long-term clinical studies. The total daily dose should be divided in three single doses, the maximum time interval between the doses should not exceed 12 hours to prevent breakthrough convulsions.
Children aged 6 years and above:
The starting dose should range from 10 to 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 aged 6 years and older is 25 to 35 mg/kg/day. Dosages up to 50 mg/kg/day have been well tolerated in a long term clinical study. The total daily dose should be divided in three single doses, the maximum time interval between doses should not exceed 12 hours.
It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy. Further, gabapentin may be used in combination with other antiepileptic medicinal products without concern for alteration of the plasma concentrations of gabapentin or serum concentrations of other antiepileptic medicinal products.
Peripheral neuropathic pain:
Adults:
The therapy may be initiated by titrating the dose as described in Table 1. Alternatively, the starting dose is 900 mg/day given as three equally divided doses. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300 mg/day increments every 2-3 days up to a maximum dose of 3600 mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of 2 weeks, and to reach 3600 mg/day is a total of 3 weeks.
In the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia, efficacy and safety have not been examined in clinical studies for treatment periods longer than 5 months. If a patient requires dosing longer than 5 months for the treatment of peripheral neuropathic pain, the treating physician should assess the patient’s clinical status and determine the need for additional therapy.
Instruction for all areas of indication:
In patients with poor general health, i.e., low body weight, after organ transplantation etc., the dose should be titrated more slowly, either by using smaller dosage strengths or longer intervals between dosage increases.
Elderly (over 65 years of age):
Elderly patients may require dosage adjustment because of declining renal function with age. Somnolence, peripheral oedema and asthenia may be more frequent in elderly patients.
Renal impairment:
Dosage adjustment is recommended in patients with compromised renal function as described in Table 2 and/or those undergoing haemodialysis. Gabapentin 100 mg capsules can be used to follow dosing recommendations for patients with renal insufficiency.
Table 2:
| Dosage of gabapentin in adults based on renal function | |
| Creatinine clearance (mL/min) | Total daily dosea (mg/day) |
| ≥ 80 | 900 – 3600 |
| 50 – 79 | 600 – 1800 |
| 30 – 49 | 300 – 900 |
| 15 – 29 | 150 b – 600 |
| < 15 c | 150 b – 300 |
- Total daily dose should be administered as three divided doses. Reduced dosages are for patients with renal impairment (Creatinine clearance < 79 mL/min).
- Dose to be administered as 300 mg every other day.
- For patients with creatinine clearance < 15 mL/min, the daily dose should be reduced in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive).
Use in patients undergoing haemodialysis:
For anuric patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400 mg, then 200 to 300 mg of gabapentin following each 4 hours of haemodialysis, is recommended. On dialysis-free days, there should be no treatment with gabapentin.
For renally impaired patients undergoing haemodialysis, the maintenance dose of gabapentin should be based on the dosing recommendations found in Table 2. In addition to the maintenance dose, an additional 200 to 300 mg dose following each 4-hour haemodialysis treatment is recommended.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling the drug after use.
Contraindications:
Hypersensitivity to gabapentin or any of excipients of this medicine.
Warnings and precautions for use:
Respiratory depression:
Gabapentin 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.
Suicidal ideation and behaviour:
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs 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 gabapentin.
Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should sign of suicidal ideation or behaviour emerge.
Anaphylaxis:
Gabapentin 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 gabapentin and seek immediate medical care should they experience signs or symptoms of anaphylaxis.
Acute pancreatitis:
If a patient develops acute pancreatitis under treatment with gabapentin, discontinuation of gabapentin should be considered.
Seizures:
Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus.
As with other antiepileptic medicinal products, some patients may experience an increase in seizure frequency or the onset of new types of seizures with gabapentin.
As with other anti-epileptics, attempts to withdraw concomitant anti-epileptics in treatment refractive patients on more than one anti-epileptic, in order to reach gabapentin monotherapy have a low success rate.
Gabapentin is not considered effective against primary generalized seizures such as absences and may aggravate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizures including absences.
Gabapentin 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 metal impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.
Concomitant use with opioids:
Patients who require concomitant treatment with opioids should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence, sedation, and respiratory depression. Patients who use gabapentin and morphine concomitantly may experience increases in gabapentin concentrations. The dose of gabapentin or opioids should be reduced appropriately.
Elderly (over 65 years of age):
No systematic studies in patients 65 years or older have been conducted with gabapentin. In one double blind study in patients with neuropathic pain, somnolence, peripheral oedema and asthenia occurred in a somewhat higher percentage in patients aged 65 years or above, than in younger patients. Apart from these findings, clinical investigations in this age group do not indicate an adverse event profile different from that observed in younger patients.
Paediatric population:
The effects of long-term (greater than 36 weeks) gabapentin therapy on learning, intelligence, and development in children and adolescents have not been adequately studied. The benefits of prolonged therapy must therefore be weighed against the potential risks of such therapy.
Abuse and dependence:
Cases of abuse and dependence have been reported in the post-marketing database. Carefully evaluate patients for a history of drug abuse and observe them for possible signs of gabapentin abuse, e.g. drug-seeking behaviour, dose escalation, development of tolerance.
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 antiepileptic drugs including gabapentin.
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. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Laboratory tests:
False positive readings may be obtained in the semi-quantitative determination of total urine protein by dipstick tests. It is therefore recommended to verify such a positive dipstick test result by 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 beginning.
Pregnancy and lactation:
Pregnancy:
Risk related to epilepsy and antiepileptic drugs (AEDs) in general:
The risk of birth defects increases by a factor of 2-3 in the offspring of mothers treated with an anti-epileptic medical product. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformation than monotherapy.
Therefore, it is important that monotherapy is practised whenever possible.
Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential and the need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant.
No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child.
Developmental delay in children of mothers with epilepsy has been observed rarely. It is not possible to differentiate if developmental delay is cause by genetic, social factors, maternal epilepsy or the antiepileptic therapy.
Risk related to gabapentin:
Gabapentin crosses the human placenta.
There are no or limited amount of data from the use of gabapentin in pregnant women.
Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. However, Gabapentin should not be use during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus.
No definite conclusion can be made as to whether gabapentin is causally associated with an increased risk of congenital malformations when taken during pregnancy, because of epilepsy itself and the presence of concomitant antiepileptic medical products during each reported pregnancy.
Women who may become pregnant or are using contraceptives or are pregnant should carefully consult their doctor before treatment with this medicine.
Lactation:
Gabapentin is excreted in human milk. Because the effect on the breast-fed infant is unknown, caution should be exercised when gabapentin is administered to a breast-feeding mother. Gabapentin should be used in breast-feeding mothers only if the benefits clearly outweigh the risks.
Fertility:
There is no effect on fertility in animal studies.
Effects on ability to drive, use machines:
Gabapentin may have minor or moderate influence on the ability to drive and use machines. Gabapentin acts on the central nervous system and may cause drowsiness, dizziness or other related symptoms.
Even, if they were only of mild or moderate degree, these undesirable effects could be potentially dangerous in patients driving or operating machinery. This is especially true at the beginning of the treatment and after increase in dose.
Interactions, incompatibilities of medicine:
Interaction of the drug with other drugs and other types of interactions:
There are spontaneous and literature case reports of respiratory depression and/or sedation associated with gabapentin and opioid use. In some of these reports, the authors considered this a particular concern with the combination of gabapentin and opioids, especially in elderly patients.
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 gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients who require concomitant treatment with opioids should be carefully observed for signs of CNS depression, such as somnolence, sedation and respiratory depression and the dose of gabapentin or opioid should be reduced appropriately.
No interaction between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine has been observed.
Gabapentin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving these antiepileptic agents.
Co-administration of gabapentin with oral contraceptives containing norethindrone and/or ethinyl estradiol, does not influence the steady-state pharmacokinetics of either component.
Co-administration of gabapentin with antacids containing aluminium and magnesium, reduces gabapentin bioavailability up to 24%. It is recommended that gabapentin be taken at the earliest two hours following antacid administration.
Renal excretion of gabapentin is unaltered by probenecid.
A slight decrease in renal excretion of gabapentin that is observed when it is co-administered with cimetidine is not expected to be of clinical importance.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Adverse reactions are ranked according to frequency: Very common (ADR > 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000), can not be estimated from the available data “Unknown”.
| System organ class | Adverse drug reactions |
| Infections and infestations | |
| Very Common | Viral infection |
| Common | Pneumonia, respiratory infection, urinary tract infection, infection, otitis media |
| Blood and the lymphatic system disorders | |
| Common | Leucopenia |
| Not Known | Thrombocytopenia |
| Immune system disorders | |
| Uncommon | Allergic reactions (e.g. urticaria) |
| Not Known | Hypersensitivity syndrome (a systemic reaction with a variable presentation that can include fever, rash, hepatitis, lymphadenopathy, eosinophilia, and sometimes other signs and symptoms), anaphylaxis. |
| Metabolism and nutrition disorders | |
| Common | Anorexia, increased appetite |
| Uncommon | Hyperglycaemia (most often observed in patients with diabetes) |
| Rare | Hypoglycaemia (most often observed in patients with diabetes) |
| Not known | Hyponatraemia |
| Psychiatric disorders | |
| Common | Hostility, confusion and emotional lability, depression, anxiety, nervousness, thinking abnormal |
| Uncommon | Agitation |
| Not known | Hallucinations |
| Nervous system disorders | |
| Very Common | Somnolence, dizziness, ataxia |
| Common | Convulsions, hyperkinesias, dysarthria, amnesia, tremor, insomnia, headache, sensations such as paresthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes |
| Uncommon | Hypokinesia, mental impairment |
| Rare | Loss of consciousness |
| Not known | Other movement disorders (e.g. choreoathetosis, dyskinesia, dystonia) |
| Eye disorders | |
| Common | Visual disturbances such as amblyopia, diplopia |
| Ear and labyrinth disorders | |
| Common | Vertigo |
| Not known | Tinnitus |
| Cardiac disorders | |
| Uncommon | Palpitations |
| Vascular disorders | |
| Common | Hypertension, vasodilatation |
| 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, dry mouth or throat, flatulence |
| Not known | Pancreatitis |
| Hepatobiliary disorders | |
| 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 |
| Not known | Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, erythema multiforme, alopecia, drug rash with eosinophilia and systemic symptoms |
| Musculoskeletal and connective tissue disorders | |
| Common | Arthralgia, myalgia, back pain, twitching |
| Not known | Rhabdomyolysis, myoclonus |
| Renal and urinary disorder | |
| Not known | Acute renal failure, incontinence |
| Reproductive system and breast disorders | |
| Common | Impotence |
| Not known | Breast hypertrophy, gynaecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia) |
| General disorders and administration site conditions | |
| Very Common | Fatigue, fever |
| Common | Peripheral oedema, abnormal gait, asthenia, pain, malaise, flu syndrome |
| Uncommon | Generalized oedema |
| Not known | Withdrawal reactions* chest pain. Sudden unexplained deaths have been reported where a causal relationship to treatment with gabapentin has not been established. |
| Investigations | |
| Common | WBC (white blood cell count) decreased, weight gain |
| Uncommon | Elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin |
| Not known | Blood creatine phosphokinase increased |
| Injury, poisoning and procedural complications | |
| Common | Accidental injury, fracture, abrasion |
| Uncommon | Fall |
Under treatment with gabapentin cases of acute pancreatitis were reported. Causality with gabapentin is unclear.
In patients on haemodialysis due to end-stage renal failure, myopathy with elevated creatine kinase levels has been reported.
Respiratory tract infections, otitis media, convulsions and bronchitis were reported only in clinical studies in children. Additionally, in clinical studies in children, aggressive behaviour and hyperkinesia were reported commonly.
Guidance on handling ADR:
Loss of coordination usually involves dosing. If dose reduction does not improve patient’s condition, gabapentin should be discontinued.
If Stevens Johnson syndrome is suspected, gabapentin should be discontinued.
Gabapentin should not be discontinued suddenly because frequency of seizures may be increased. The dose should be tapered at least 7 days before stopping gabapentin or taking other anticonvulsant medications.
Overdose and management:
Overdose:
Acute, life-threatening toxicity has not been observed with gabapentin overdoses of up to 49 grams. Symptoms of the overdoses included dizziness, double vision, slurred speech, drowsiness, loss of consciousness, lethargy and mild diarrhoea.
Overdoses of gabapentin, particularly in combination with other CNS depressant medications, may result in coma.
Although gabapentin can be removed by haemodialysis, based on prior experience it is not usually required. However, in patients with severe renal impairment, haemodialysis may be indicated.
An oral lethal dose of gabapentin was not identified in mice and rats given doses as high as 8000 mg/kg.
Signs of acute toxicity in animals included ataxia, laboured breathing, ptosis, hypoactivity, or excitation.
Management:
All patients recovered fully with supportive case. Reduced absorption of gabapentin high doses may limit drug absorption at the time of overdosing and, hence, minimize oxicity from overdose.
Although gabapentin can be removed by hemodialysis, based on prior experience it is usually not required. However, in patients with severe renal impairment, hemodialysis may be indicated.
Pharmacodynamics:
Pharmacological group: Antiepileptic drugs for treatment of neuropathic pain.
ATC code: N03AX12.
Gabapentin is a medication used to treat epilepsy, neuropathic pain, the mechanism of actions is unknown. In experimental studies in animals, gabapentin exhibits antiseizure activity after electroshocks and also inhibits pentylenetetrazole-induced seizures. The effect obtained from experiment is similar to valproic acid but different from phenytoin and carbamazepine. The chemical structure of gabapentin is similar to gamma-aminobutyric acid (GABA), a neurotransmitter inhibitor, but gabapentin does not directly act on GABA receptors, does not alter the structure, release, metabolism and absorption GABA.
High affinity gabapentin binding sites have been located throughout the brain; these sites correspond to the presence of voltage-gated calcium channels specifically possessing the alpha-2-delta-1 subunit. This channel appears to be located presynaptically, and may modulate the release of excitatory neurotransmitters, which participate in epileptogenesis and nociception.
Pharmacokinetics:
Absorption: Gabapentin is absorbed from the gastrointestinal tract via a saturable uptake mechanism (this means that at saturated leves, increases in dosage do not greatly increase drug uptake). Peak plasma concentrations occur 2-3 hours after oral administration and reach steady state after 1-2 days. The effective serum concentrations of gabapentin have not been determined. However, in one study it was noted that decreased seizure frequency was only observed in patients with gabapentin serum concentrations > 2 mg/L (11.7 micromoles/L). Plasma concentrations of gabapentin generally range from 2 mg/L (2 micrograms/ml) to 20 mg/L (20 micrograms/ml).
Bioavailability is approximately 60% for 900 mg daily. Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases (bioavailability is approximately 27% for a 4.8 g daily dose). Food has only a slight effect on the rate and extent of absorption of gabapentin.
Distribution: Gabapentin is distributed throughout the body, excreted into breast milk, binding to plasma protein very low (< 3%). The distribution volume of gabapentin is 58 ± 6 liters in adults.
Metabolism, elimination: Gabapentin is not virtually metabolized in humans and is almost entirely excreted unchanged via the kidneys. Half life of gabapentin is about 5 to 7 hours in people with normal kidney function, 132 hours in patients with anuria, 3.8 hours during dialysis.
Gabapentin does not alter the pharmacokinetics of commonly used anticonvulsants (such as carbamazepine, phenytoin, valproate, phenobarbital, diltiazem) or oral contraceptives. In addition, the pharmacokinetics of gabapentin are not significantly altered by simultaneous administration of other anticonvulsants.
Higher oral clearance values were observed in children < 5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The normalized clearance values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. Therefore, in children 3 to 5 years of age, higher daily doses should be used to achieve average plasma concentrations similar to those achieved in children aged ≥ 5 years. The clearance was highly variable in infants < 1 year of age.
Storage conditions, shelf life, quality specification of the medicine:
Storage conditions: Protect from humidity and light, below 300C.
Shelf life: 36 months from the manufacture date.
Quality specification: In house.
A1203024501
