Consumer medicine information

Gabapentin APOTEX Capsules

Gabapentin

BRAND INFORMATION

Brand name

Gabapentin APOTEX Capsules

Active ingredient

Gabapentin

Schedule

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about gabapentin. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

if there is anything you do not understand in this leaflet,
if you are worried about taking your medicine, or
to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is Gabapentin APOTEX capsules. It contains the active ingredient, gabapentin.

control epilepsy, a condition that causes repeated seizures (fits). There are many different types of seizures, ranging from mild to severe
treat neuropathic pain (pain due to nerves being damaged or affected).

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

How it works

Gabapentin belongs to a group of medicines called anticonvulsants.

It is thought to work by controlling brain chemicals which send signals to nerves to help control seizures or neuropathic pain.

This medicine helps to relieve pain.

Your doctor may prescribe gabapentin in addition to your current treatment when your current treatment is no longer working as well.

Your doctor may have prescribed Gabapentin for another reason.

Gabapentin may lead to dependence on this medicine.

Ask your doctor if you have any question about why Gabapentin has prescribed for you.

This medicine is available only with a doctor's prescription.

Use in children

There is not enough information the use of this medicine in children under the age of:

3 years to control epilepsy
18 years for the treatment of neuropathic pain.

Before you take this medicine

When you must not take it

Do not take this medicine if:

You are hypersensitive to or have had an allergic reaction to gabapentin or any of the ingredients listed at the end of this leaflet.
Symptoms of an allergic reaction may include:
- shortness of breath
- wheezing or difficulty breathing.
- swelling of the face, lips, tongue or other parts of the body
- rash, itching or hives on the skin.
If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
The expiry date (EXP) printed on the pack has passed.
The packaging is torn, shows signs of tampering or it does not look quite right.
If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking Gabapentin, talk to your doctor or pharmacist.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

any other medicines, especially barbiturates or any other anticonvulsant medicine.
any other substances, such as foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

kidney problems
mixed seizure disorders that include absence seizure

Tell your doctor if you have a history of drug abuse. Gabapentin poses risks of abuse and dependence. Your body may become used to you taking Gabapentin and this may result in physical dependence. It means that you may experience withdrawal symptoms if you stop taking Gabapentin suddenly. So it is important to strictly follow the directions given by your doctor.

Tell your doctor if you are pregnant or plan to become pregnant. Gabapentin may affect your developing baby if you take it during pregnancy. However, it is very important to control your fits while you are pregnant. If it is necessary for you to take this medicine your doctor can help you decide whether or not to take it during pregnancy.

Tell your doctor if you are breastfeeding or plan to breast-feed. Gabapentin passes into breast milk. The effect on your breast-fed baby is unknown.

If you do breast-feed, watch your baby carefully. If your baby develops a skin rash, becomes sleepy or has unusual symptoms, don't breast-feed again until you speak to your doctor.

Your doctor can discuss the risks and benefits of breast-feeding with you.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Gabapentin.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including:

all prescription medicines
all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by Gabapentin or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor or pharmacist will advise you accordingly.

Gabapentin and certain other medicines may influence each other.

Using Gabapentin with other medicines that can make you feel drowsy, such as sleeping tablets and other pain relievers (e.g., benzodiazepines and opioids), antihistamines, antidepressants, antipsychotics, cannabis, and alcohol may result in severe drowsiness, decreased awareness, breathing problems, coma and death. Your doctor will minimise the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation.

Tell your doctor or pharmacist if you are taking any of the following:

cimetidine, a medicine used to treat stomach or duodenal ulcers, or reflux
antacids, medicines used to treat heartburn or reflux.
opioids, medicines used to treat severe pain e.g. morphine.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Gabapentin.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

If you do not understand any written instructions, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much of this medicine you should take. This may depend on your age, your condition and whether you are taking any other medicines.

Your doctor may recommend that you start with a low dose of gabapentin and then slowly increase the dose to the lowest amount needed to control your epilepsy or neuropathic pain.

Do not stop taking your medicine or change your dosage unless instructed without first checking with your doctor.

How to take it

Swallow gabapentin capsules with a full glass of water.

When to take it

Take this medicine at the same time each day.

Taking it at the same time each day will have the best effect and will also help you remember when to take it. If you are taking gabapentin three times a day, do not allow more than 12 hours between doses.

It does not matter if you take it before, with or after food.

If you need to take an antacid, take it at least 2 hours before or 2 hours after your dose of this medicine.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

This medicine helps control your condition but does not cure it. Therefore, you must take it every day, even if you feel well.

Do not stop taking Gabapentin, or lower the dose, without checking with your doctor.

Make sure you have enough to last over weekends and holidays.

Stopping Gabapentin suddenly may worsen your condition or increase your chances of experiencing withdrawal symptoms, such as sleeplessness, headache, nausea (feeling sick), anxiety, excessive sweating or diarrhoea (runny stools). If appropriate, your doctor will slowly reduce your dose before you can stop taking it completely.

If you forget to take it

If it is almost time for your next dose (within 4 hours), skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much gabapentin, you falling unconscious, feeling drowsy, weak, and unsteady when walking, have double vision, slurred speech or diarrhoea.

While you are taking this medicine

Things you must do

If you are about to be started any new medicine, remind your doctor and pharmacist that you are taking Gabapentin.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking Gabapentin.

If you are going to have surgery or emergency treatment, tell the surgeon or anaesthetist that you are taking Gabapentin.

Tell your doctor immediately if you have any thoughts of suicide or self-harm, any unusual changes in modd or behaviour, or show signs of depression.

Some people being treated with antiepileptic, such as Gabapentin, have thoughts of harming or killing themselves.

Patients and caregivers should be alert and monitor for signs and symptoms of suicide, these includes:

thoughts or talk of death or suicide
thoughts or talk of self-harm or harm to others
any recent attempts of self-harm
new or an increase in aggressive behaviour, irritability or agitation
new onset of or worsening of depression.

Mention of suicide or violence must be taken seriously.

If you or someone you know is demonstrating these warnings signs and symptoms of suicide while taking Gabapentin, contact your doctor or a mental health professional right away.

Tell your doctor if you feel Gabapentin is not helping your condition. Your doctor may need your medicine.

Tell your doctor if, for any reason, you have not taken Gabapentin exactly as prescribed. Otherwise, your doctor may change your treatment unnecessarily.

If you become pregnant while taking Gabapentin, tell your doctor immediately.

If you need to have any medical tests while you are taking Gabapentin, tell your doctor. It may interfere with the results of some tests.

If you are going to have any surgery or procedure, including dental surgery, tell your surgeon, doctor or dentist that you are taking this medicine.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor will check your progress and may want to take some tests from time to time. This helps to prevent unwanted side effects.

Things you must not do

Do not give this medicine to anyone else, even if their symptoms seem similar to yours or they have the same condition as you.
Do not take your medicine to treat any other condition unless your doctor tells you to.
Do not stop taking your medicine, or lower the dosage, without first checking with your doctor.
Stopping gabapentin suddenly, if you have epilepsy, may cause unwanted effects or make your condition worse. Your doctor will slowly reduce your dose before you can stop taking it completely.

Things to be careful of

Be careful driving or operating machinery until you know how Gabapentin affects you. As with other anticonvulsant medicines, Gabapentin may cause drowsiness, dizziness, light-headedness or sleepiness in some people. Make sure you know how you react to Gabapentin before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive.

Children should not ride a bike, climb trees or do anything else that could be dangerous if they are feeling drowsy or sleepy.

Be careful when drinking alcohol while you are taking Gabapentin. Combining Gabapentin and alcohol can make you more sleepy, dizzy or light-headed. Your doctor may suggest you avoid alcohol while you are being treated with Gabapentin.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking gabapentin or if you have any questions or concerns.

All medicines can have side effects. Sometimes they are serious, but most of the time, these are not. You may need medical attention if you get some side effects.

It can be difficult to tell whether side effects are the result of taking Gabapentin, of your condition; or side effects of other medicines you may be taking for this reason it is important to tell your doctor of any change in your condition.

If you are over 65 years of age you may have an increased chance of getting side effects.

Ask your doctor or pharmacist to answer any questions you may have.

If you get any side effects, do not stop taking gabapentin without first talking to your doctor or pharmacist.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

dizziness* or light-headedness
feeling tired or drowsy*
unfriendliness*
unusually overactive*
feeling agitated
forgetfulness, loss of concentration or confusion
difficulty speaking
changes in your weight*
constipation, diarrhoea
nausea and/or vomiting*, indigestion
dry mouth, red swollen gums
muscle pain or cramps, back pain
swelling of the hands or feet or blocked nose
fever*
bronchitis*, lung infection*
sore throat and discomfort when swallowing, coughing.

The above list includes the more common side effects of Gabapentin. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following.

weakness, unsteadiness when walking including falling, reduced coordination or slowed reactions
unusual changes in mood* or behaviour such as restlessness, nervousness or excitement
signs of new onset of, or increased irritability or agitation
signs of depression
seeing or hearing things that are not there, irrational thinking
blurred or double vision, uncontrollable jerky eye movements, difficulty seeing
signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers.
trouble breathing or shallow breaths (respiratory depression)
loss of consciousness

The side effects in the above list marked * have been specifically reported in children taking gabapentin.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

more frequent or more severe seizures (fits)
chest pain, a very fast heart rate
sudden signs of allergy such as rash, itching or hives, fever, swollen lymph glands, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty breathing

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some patients.

Some of these side effects (for example, changes in thyroid function, structures of bones, high cholesterol, levels of sugar in your blood or blood pressure) can only be found when your doctor does blood tests from time to time to check your progress.

Do not be alarmed by the list of possible effects. You may not experience any of them.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging, it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C. Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine, or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product Description

What Gabapentin APOTEX capsules look like

Gabapentin capsules are available in 100 mg, 300 mg and 400 mg strengths.

Gabapentin 100 mg Capsules:
White/White coloured size ‘3’ hard gelatin capsules, filled with white to off-white blend.

Gabapentin 300 mg Capsules:
Yellow/Yellow coloured size ‘0’ with cap ‘M’ and body ‘300’ printed with black ink, hard gelatin capsules, filled with white to off-white blend.

Gabapentin 400 mg Capsules:
Orange/Orange coloured size ‘0el’ with cap ‘M’ and body ‘400’ printed with black ink, hard gelatin capsules, filled with white to off-white blend.

Available in blister packs of 10, 20, 30, 50, 100, 150, 300, 500, 1000 capsules.

Not all strengths, pack sizes and/or pack types may be available.

Ingredients

Active Ingredient:

Each capsule contains 100 mg, 300 mg or 400 mg of gabapentin as the active ingredient.

It also contains the following inactive ingredients:

lactose monohydrate
talc-purified
starch maize
gelatin
titanium dioxide
sodium lauryl sulfate
iron oxide - yellow (300 mg / 400 mg)
iron oxide - red (400 mg)
purified water.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes-free.

This medicine contains sugars as lactose monohydrate. May contain trace amounts of phenylalanine and sulfites.

Australian Registration Numbers

Gabapentin APOTEX 100 mg Capsules (blister pack): AUST R 304223

Gabapentin APOTEX 300 mg Capsules (blister pack): AUST R 304224

Gabapentin APOTEX 400 mg Capsules (blister pack): AUST R 304225

Sponsor

This medicine is sponsored in Australia by

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park, NSW 2113
Australia
Tel: (02) 8877 8333
Web: www1.apotex.com/au

APOTEX is a registered trademark of Apotex Inc.

This leaflet was prepared in:
November 2021.

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Gabapentin APOTEX Capsules

Active ingredient

Gabapentin

Schedule

1 Name of Medicine

Gabapentin.

2 Qualitative and Quantitative Composition

Each capsule contains 100 mg, 300 mg or 400 mg of gabapentin.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

100 mg capsules.

White/White coloured size '3' hard gelatin capsules, filled with white to off-white blend.

300 mg capsules.

Yellow/Yellow coloured size '0' with cap 'M' and body '300' printed with black ink hard gelatin capsules, filled with white to off-white blend.

400 mg capsules.

Orange/Orange coloured size '0el' with cap 'M' and body '400' printed with black ink hard gelatin capsules, filled with white to off-white blend.

4 Clinical Particulars

4.1 Therapeutic Indications

Gabapentin is indicated for the treatment of partial seizures, including secondarily generalised tonic-clonic seizures, initially as add-on therapy in adults and children age 3 years and above who have not achieved adequate control with standard antiepileptic drugs.
Gabapentin is indicated for the treatment of neuropathic pain.

4.2 Dose and Method of Administration

Dosage.

Epilepsy.

Dosage for adults and children over 12 years of age.

Initiation of treatment should be as add-on therapy. Gabapentin can be given orally with or without food.
In controlled clinical trials, the effective dose range was 900 mg/day to 1800 mg/day given in divided doses (three times a day).
Therapy may be initiated by administering 300 mg of gabapentin capsules three times a day on Day 1, as 300 mg capsules, or by titrating the dose as described below.
Titration to an effective dose can take place rapidly, over a few days, giving 300 mg gabapentin on Day 1, 300 mg gabapentin twice a day on Day 2, 300 mg gabapentin three times a day on Day 3 as 300 mg capsules. Titration may be preferable for patients with renal impairment, patients with encephalopathy, patients on more than 2 other antiepileptic drugs and patients with multiple other medical problems.
To minimise potential side effects, especially somnolence, dizziness, fatigue and ataxia, the first dose on Day 1 may be administered at bedtime. If necessary, the dose may be increased using 300 or 400 mg capsules three times a day up to 2400 mg/day. Dosages up to 2400 mg/day have been well tolerated in long-term open-label clinical studies.
The maximum time between doses in the three times a day schedule should not exceed 12 hours.

Neuropathic pain in adults (over 18 years of age).

The starting dose is 900 mg/day given as three daily divided doses and titrated if necessary, based on response, up to a maximum dose of 3600 mg/day.

Dosage for children aged 3 to 12 years of age.

The effective dose of gabapentin is 25 mg/kg/day to 35 mg/kg/day given in three divided doses (3 times a day). Titration to an effective dose can take place over 3 days by giving 10 mg/kg/day on Day 1, 20 mg/kg/day on Day 2, and 30 mg/kg/day on Day 3. Dosages up to 40 mg/kg/day to 50 mg/kg/day have been well tolerated in a long-term clinical study. Doses of 60 mg/kg/day have also been administered to a small number of children.

Dosage adjustment.

Dose adjustment in impaired renal function for patients with neuropathic pain or epilepsy.

Dose adjustment is recommended in patients with compromised renal function and/or those undergoing haemodialysis (see Table 1).

For patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400 mg is recommended, then 200 to 300 mg of gabapentin following each 4 hours of haemodialysis.
Unlike other agents in this class, it is not necessary to monitor gabapentin plasma concentrations to optimise gabapentin therapy. Further, gabapentin may be used in combination with other antiepileptic drugs without concern for alteration of the plasma concentrations of gabapentin or serum concentrations of other antiepileptic drugs.

Discontinuation of gabapentin.

If gabapentin is discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of one week (see Section 4.4 Special Warnings and Precautions for Use, Discontinuation).

4.3 Contraindications

Gabapentin capsules are contraindicated in patients who have demonstrated hypersensitivity to gabapentin or to any of the inactive ingredients in the capsules.

4.4 Special Warnings and Precautions for Use

General.

Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus. When in the judgement of the clinician there is a need for dose reduction, discontinuation, or substitution of alternative anticonvulsant medication, this should be done gradually over a minimum of one week.
Gabapentin is generally not considered effective in the treatment of absence seizures and may exacerbate these seizures in some patients. Consequently, gabapentin should be used with caution in patients who have mixed seizure disorders that include absence seizures.
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 mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.

Central nervous system depression.

Respiratory depression.

Gabapentin has been associated with central nervous system (CNS) depression including sedation, somnolence, loss of consciousness as well as serious cases of respiratory depression. This may occur without concomitant opioid use. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment and the elderly are at higher risk of experiencing these severe adverse effects. Concomitant use of CNS depressants including opioids with gabapentin increases the risk of respiratory depression.

Concomitant use with opioids and other CNS depressants.

Patients who require concomitant treatment with opioids may experience increases in gabapentin concentrations. Concomitant use of opioids may result in severe sedation, respiratory depression, coma and death. Limit dosages and durations of gabapentin to the minimum required to achieve desired therapeutic effect. Patients who require concomitant treatment with CNS depressants, including opioids, should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence, sedation and respiratory depression; and the dose of gabapentin or concomitant treatment with CNS depressants including opioids should be reduced appropriately (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Concomitant use with opioids).
Caution is advised when prescribing gabapentin 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 gabapentin 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]).

Suicidal behaviour and ideation.

Antiepileptic drugs (AEDs), including gabapentin, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing gabapentin or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour or thoughts about self-harm. Behaviours of concern should be reported immediately to the treating doctor.

Drug rash with eosinophilia and systemic symptoms.

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 aetiology for the signs or symptoms cannot be established.

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.

Abuse potential or dependence.

Gabapentin is a potential drug of abuse and dependence.
There have been post market reports of overdose and deaths among users of gabapentin, particularly with concomitant use of other sedating medicines, such as opioids and/or benzodiazepines.
The risk of abuse of gabapentin should particularly be monitored among current or past opioid and/or benzodiazepine users.
Patients should be carefully evaluated for a history of substance abuse prior to being prescribed gabapentin and observed for signs of gabapentin abuse (e.g. development of tolerance, increase in dose, drug seeking behaviour).

Discontinuation.

Withdrawal symptoms have been observed in some patients after discontinuation of gabapentin, including severe symptoms in patients taking high doses. Withdrawal symptoms after discontinuation of both short-term and long-term treatment with gabapentin have been observed in some patients. The following events have been mentioned: insomnia, headache, nausea, anxiety, hyperhidrosis and diarrhoea. Discontinuation should be done gradually over a minimum of one week (see Section 4.2 Dose and Method of Administration, Discontinuation of gabapentin).

Information for patients.

To assure safe and effective use of gabapentin, the following information and instructions should be given to patients:
1. You should inform your physician about any prescription or non-prescription medications, alcohol, or drugs you are now taking or are planning to take during your treatment with gabapentin.
2. No teratogenic effects have been found in animals. However, the risk to the human fetus cannot be dismissed. Therefore, you should inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking gabapentin.
3. Gabapentin is excreted in human milk, and the effect on the nursing infant is unknown. You should inform your physician if you are breast feeding an infant.
4. Gabapentin may impair your ability to drive a car or operate potentially dangerous machinery. Until it is known that this medication does not affect your ability to engage in these activities, do not drive a car or operate potentially dangerous machinery.
5. You should not allow more than 12 hours between gabapentin doses. If you have missed a dose by not more than 4 hours, take the dose as soon as you remember. However, if you have missed a dose by more than 4 hours, you should skip the dose and continue taking following doses as usual.
6. Prior to initiation of treatment with gabapentin, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity such as fever or lymphadenopathy may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Central nervous system depression.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use, Central nervous system depression.

Paediatric use.

Epilepsy.

Safety and effectiveness in children below the age of 3 years have not been established.

Neuropathic pain.

Safety and effectiveness in children below the age of 18 years have not been established.

Effects on laboratory tests.

False positive readings were reported with the Ames N-Multistix SG dipstick test when gabapentin was added to other anticonvulsant medicines. To determine urinary protein, the more specific sulfosalicylic acid precipitation procedure is recommended.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There are spontaneous and literature case reports of respiratory depression and/or sedation associated with gabapentin when co-administered with CNS depressants, including opioids. In some of these reports, the authors considered the combination of gabapentin 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 patients with substance abuse disorders.

Anticonvulsants.

In pharmacokinetic studies, no interactions were observed between gabapentin and phenobarbital (number of subjects, N = 12), phenytoin (N = 8), valproic acid (N = 17) or carbamazepine (N = 12).

Oral contraceptives.

Gabapentin did not influence the steady-state pharmacokinetics of norethindrone and ethinyloestradiol when administered concomitantly with an oral contraceptive containing these two medicines (N = 13).

Antacid.

Co-administration of gabapentin with large dose antacid (aluminium hydroxide 3600 mg, magnesium hydroxide 1800 mg) reduced gabapentin bioavailability (AUC) by about 20% (N = 16). Although the difference was not expected to be clinically significant, it is recommended that gabapentin should be taken about 2 hours following antacid administration, when the interaction has been shown to be diminished.

Cimetidine.

In the presence of cimetidine at 300 mg, four times a day (QID), the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance by 10% (N = 12). Thus cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function.

Probenecid.

Renal excretion of gabapentin was unaltered by probenecid, a blocker of renal tubular secretion.

Concomitant use with opioids.

In post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking gabapentin and other CNS depressant medications including opioids, and in patients who have a history of substance abuse (see Section 4.4 Special Warnings and Precautions for Use, Concomitant use with opioids and other CNS depressants).

Morphine.

A literature article reported that when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule (N = 12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine (see Section 4.4 Special Warnings and Precautions for Use). Morphine pharmacokinetic parameter values were not affected by administration of gabapentin 2 hours after morphine. The magnitude of interaction at other doses is not known.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg/day administered in the diet, with estimated exposure (plasma AUC) 14 times clinical exposure at the MRHD of 2400 mg/day.
(Category B3)
Gabapentin crosses the human placenta.
Congenital malformations and adverse pregnancy outcomes have been reported with gabapentin use, however, there are no adequate and well-controlled studies in pregnant women and no definite conclusions can be made as to whether gabapentin is causally associated with an increased risk of congenital malformations or other adverse developmental outcomes when taken during pregnancy. The risk of birth defects is increased by a factor of 2-3 in the offspring of mothers treated with an anti-epileptic medicinal product. Gabapentin should be used during pregnancy only if the potential benefit to the mother clearly outweighs the potential risk to the fetus.
The risk of having a child with a congenital defect as a result of antiepileptic medication is far outweighed by the dangers to the mother and fetus of uncontrolled epilepsy.
It is recommended that:
women on antiepileptic drugs (AEDs) receive pre-pregnancy counselling with regard to the risk of fetal abnormalities;
AEDs should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication;
folic acid supplementation (5 mg) should be commenced four weeks prior to and continue for twelve weeks after conception;
specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered.
Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.
Embryofetal development studies with gabapentin in mice at oral doses up to 3000 mg/kg/day and in rats at oral doses up to 1500 mg/kg/day revealed no evidence of fetal malformations. Delayed ossification in the skull, vertebrae and limbs, indicative of fetal growth retardation, was reported in the offspring of mice administered gabapentin at oral doses of 1000 and 3000 mg/kg/day during organogenesis, and rats administered gabapentin 2000 mg/kg/day in the diet during mating and throughout gestation. An increased incidence of hydroureter and/or hydronephrosis was observed in rats treated with dietary gabapentin from late gestation to weaning (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation). In these studies, exposure to gabapentin (based on areas under the concentration time curve) was up to 5 times higher in the mouse, and up to 14 times higher in the rat, than in humans at the recommended maximum dose of 2400 mg/day.
In female rabbits given 60, 300 or 1500 mg/kg/day gabapentin orally during the period of organogenesis, maternal toxicity and abortion were observed at the high dose, but at the low and mid doses, no evidence of harm to the fetus was observed.
Gabapentin is excreted in human milk.
In a peri-postnatal study in rats administered gabapentin in the diet at doses of 500, 1000 and 2000 mg/kg/day from late gestation to weaning, there was a dose related reversible increase in the incidence of hydroureter and hydronephrosis in 21 day-old pups.
Because the effect on the nursing infant is unknown and because of the potential for serious adverse reactions in nursing infants from gabapentin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Gabapentin should be used in nursing mothers only if the benefits clearly outweigh the risks.

4.7 Effects on Ability to Drive and Use Machines

Patients should be advised not to drive a car or operate potentially dangerous machinery until it is known that gabapentin does not affect their ability to engage in these activities.

4.8 Adverse Effects (Undesirable Effects)

Adults and children over 12 years of age with epilepsy.

Gabapentin has been evaluated for safety in approximately 2000 subjects and patients and was well tolerated. Of these, 543 patients participated in controlled clinical trials.
The most commonly observed adverse events associated with the use of gabapentin in combination with other antiepileptic drugs, not seen in an equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue and nystagmus.
Approximately 7% of the 2074 individuals who received gabapentin in the pre-marketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were somnolence, ataxia, fatigue, nausea and/or vomiting and dizziness.

Incidence in controlled epilepsy clinical trials.

Table 3 lists the treatment-emergent signs and symptoms that occurred in at least 1% of gabapentin-treated patients with epilepsy participating in gabapentin placebo-controlled trials. In these studies, either gabapentin or placebo was added to the patient's current antiepileptic drug therapy. Adverse events were usually mild to moderate in intensity.

Other adverse events observed during all epilepsy clinical studies.

Those events that occurred in at least 1% of the study participants with epilepsy who received gabapentin as adjunctive therapy in any clinical study and that are not described in the previous section as frequently occurring treatment-emergent signs and symptoms during placebo-controlled studies are summarised below.

Body as a whole.

Asthenia, malaise, facial oedema.

Cardiovascular system.

Hypertension.

Digestive system.

Flatulence, anorexia, gingivitis.

Haematologic and lymphatic systems.

Purpura most often described as bruises resulting from physical trauma.

Musculoskeletal system.

Arthralgia.

Nervous system.

Vertigo, hyperkinesia, increased, decreased or absent reflexes, paraesthesia, anxiety, hostility.

Respiratory system.

Pneumonia.

Urogenital system.

Urinary tract infection.

Special senses.

Abnormal vision, most often described as a visual disturbance.

Children from 3 to 12 years of age with epilepsy.

The most commonly observed adverse events reported with the use of gabapentin in combination with other antiepileptic drugs in children 3 to 12 years of age, not seen in equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or vomiting and somnolence.
Approximately 8% of the 292 children aged 3 to 12 years who received gabapentin in pre-approval clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal in children were somnolence (1.4%), hyperkinesia (1.0%) and hostility (1.0%). See Table 4.

Other events in more than 2% of children but equally or more frequent in the placebo group included: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhoea, anorexia, coughing and otitis media.
Adverse events occurring during clinical trials in children treated with gabapentin that were not reported in adjunctive therapy trials in adults are:

Body as a whole.

Dehydration, infectious mononucleosis.

Digestive system.

Hepatitis, oral moniliasis.

Haematologic and lymphatic system.

Coagulation defect.

Nervous system.

Aura disappeared, occipital neuralgia.

Psychobiologic function.

Sleepwalking.

Respiratory system.

Pseudo-croup, hoarseness.

Adults over 18 years of age with neuropathic pain.

The most commonly observed adverse events reported with the use of gabapentin in adults over 18 years of age with neuropathic pain, seen in at least twice the frequency among placebo-treated patients were dry mouth, peripheral oedema, weight gain, abnormal gait, amnesia, ataxia, confusion, dizziness, hypoaesthesia, somnolence, thinking abnormal, vertigo, rash and amblyopia.
Of the 821 adults who received gabapentin in the painful diabetic peripheral neuropathy and post-herpetic neuralgia trials, 13.2% discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were dizziness (4.4%), somnolence (2.9%) and nausea (1.3%). See Table 5.

Post-marketing experience.

The following adverse events have been reported in patients receiving gabapentin post-marketing, however, the data are insufficient to support an estimate of their incidence or to establish causation.
Sudden, unexplained deaths have been reported where a causal relationship to treatment with gabapentin has not been established. Additional post-marketing adverse events reported include blood creatine phosphokinase increased, rhabdomyolysis, abnormal liver function, acute kidney failure, allergic reaction including urticaria, alopecia, anaphylaxis, anaemia, angioedema, hyperglycaemia and hypoglycaemia (most often observed in patients with diabetes), breast hypertrophy, gynaecomastia, cardiac arrest, chest pain, convulsions, depersonalisation, drug rash with eosinophilia and systemic symptoms, erythema multiforme, fall, hypersensitivity including systemic reactions, hyponatraemia, jaundice, loss of consciousness, movement disorders such as choreoathetosis, dyskinesia and dystonia, myoclonus, palpitation, pancreatitis, renal impairment, speech disorder, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia), Stevens-Johnson syndrome, tachycardia, thrombocytopenia, tinnitus, urinary incontinence and symptoms of psychosis such as delusions, hallucinations and thinking abnormal.
Generalised oedema, hepatitis, hypotension, neuropathy/peripheral neuropathy and syncope have been rarely reported.
Adverse events following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating.
Some cases of hypomania have been reported after commencement of gabapentin. In each case, other anticonvulsants had been used concurrently and symptoms of hypomania resolved following a reduction in dosage or cessation of the drug.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

Symptoms of an overdose included somnolence, ataxia, dizziness, double vision, nystagmus, slurred speech, drowsiness, loss of consciousness, lethargy, mild hypotension and gastrointestinal symptoms including diarrhoea. Gabapentin overdose alone has not been reported to produce significant cardiotoxicity.
Overdoses as high as 108 g have been reported with full recovery following symptomatic therapy. Reduced absorption of gabapentin at higher doses may limit drug absorption at the time of overdosing and, hence, minimise toxicity from overdoses.

Treatment of overdosage.

There is no specific antidote for gabapentin; treatment is symptomatic. The patient should be monitored closely and given supportive care where necessary to maintain vital functions.
Overdoses may involve other concurrent medications and should be treated accordingly.
Activated charcoal may reduce absorption of gabapentin if given within one hour after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected.
Gabapentin can be removed by haemodialysis. Although haemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient's clinical state or in patients with significant renal impairment.
Ipecac-induced emesis is not recommended because of the potential for CNS depression.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism by which gabapentin exerts its anticonvulsant action is unknown. Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but its mechanism of action is different from that of several other drugs that interact with GABA synapses including valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists and GABA prodrugs. In vitro studies with radiolabelled gabapentin have characterised a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may relate to anticonvulsant activity of gabapentin and its structural derivatives. However, the identification and function of the gabapentin binding site remains to be elucidated. Gabapentin at relevant clinical concentrations does not bind to other common drug or neurotransmitter receptors of the brain including GABA_A, GABA_B, benzodiazepine, glutamate, glycine or N-methyl-d-aspartate receptors.
Gabapentin does not interact with sodium channels in vitro and so differs from phenytoin and carbamazepine. Several test systems ordinarily used to assess activity at the NMDA receptor complex have been examined. Results are contradictory. Accordingly, no general statement about the effects, if any, of gabapentin at the NMDA receptor can be made. Gabapentin slightly reduces the release of monoamine neurotransmitters in vitro. Gabapentin administration to rats increases GABA turnover in several brain regions in a manner similar to valproate sodium, although in different regions of brain. The relevance of these various actions of gabapentin to the anticonvulsant effects remains to be established. In animals, gabapentin readily enters the brain and shows efficacy in some, but not all, seizure models. These animal models included genetic models of seizures and seizures induced by maximal electroshock, from chemical convulsants including inhibitors of GABA synthesis.

Clinical trials.

Partial seizures.

Adults.

The effectiveness of gabapentin as adjunctive therapy was established in three multi-centre, placebo-controlled, double-blind, parallel-group clinical trials in 705 adults with refractory partial seizures. The patients enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug regimen during a 12-week baseline period. In patients continuing to have at least 2 (or 4 in some studies) seizures per month, gabapentin or placebo was then added on to the existing therapy during a 12-week treatment period. Effectiveness was assessed primarily on the basis of the percent of patients with a 50% or greater reduction in seizure frequency from baseline to treatment (the "responder rate") and a derived measure called response ratio, a measure of change defined as (T-B)/(T+B), where B is the patient's baseline seizure frequency and T is the patient's seizure frequency during treatment. Response ratio is distributed within the range -1 to +1. A zero value indicates no change while complete elimination of seizures would give a value of -1. Increased seizure rates would give positive values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The results given below are for all partial seizures in the intent-to-treat population (all patients who received any doses of treatment) in each study, unless otherwise indicated.
One study compared gabapentin 1200 mg/day, given as three divided doses (divided TID) with placebo. Responder rate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. Response ratio was also better in the gabapentin group (-0.199) than in the placebo group (-0.044), a difference that also achieved statistical significance.
A second study compared primarily gabapentin 1200 mg/day (N = 101) given as three divided doses, with placebo (N = 98). Additional smaller gabapentin dosage groups (600 mg/day, N = 53; 1800 mg/day, N = 54) were also studied for information regarding dose response. Responder rate was higher in the gabapentin 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically significant. The responder rate at 600 mg (17%) was also not significantly higher than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio was better in the gabapentin 1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not statistically significant (p = 0.224). A better response was seen in the gabapentin 600 mg/day group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to the placebo group.
A third study compared gabapentin 900 mg/day, given as three divided doses (N = 111) and placebo (N = 109). An additional gabapentin 1200 mg/day dosage group (N = 52) provided dose-response data. A statistically significant difference in responder rate was seen in the gabapentin 900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio was also statistically significantly superior in the gabapentin 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day gabapentin (-0.184) compared to placebo.
A one week, prospective, multi-centre, randomised, double-blind, placebo lead-in, parallel-group study compared the tolerability of gabapentin administered as an initial dosage of 900 mg/day versus a dosage titrated to 900 mg/day over three days (i.e. 300 mg on Day 1, 600 mg on Day 2, 900 mg on Day 3). 781 patients (titrated = 383, non-titrated = 388) involved in the study had partial seizures which were not adequately controlled with one or two other antiepileptic drugs. For the MITT population, on both the first day of active medication and all 5 days of active medication, there were no clinically meaningful treatment group differences in the incidences of fatigue, ataxia and somnolence (i.e. the upper 95% confidence limit for the difference < 7.5%). Only the difference in dizziness exceeded this upper confidence limit (upper confidence limit = 10.7% for the first day and 11.3% for all 5 days), with the non-titrated group reporting the higher incidence, however, it did not lead to increased discontinuation in this group.

Paediatrics.

The safety and efficacy of gabapentin administered as adjunctive therapy for the treatment of partial seizures in paediatric patients aged 3 to 12 years were assessed in two randomised, double-blind, parallel-group, placebo-controlled, multi-centre clinical studies. The studies were conducted in 247 children who had refractory partial seizures and were receiving 1 to 3 standard antiepileptic drugs. After a 6-week baseline phase, during which patients received their prescribed antiepileptic drugs, there was a 12-week double-blind treatment phase. Patients who had experienced a minimum of 4 seizures during baseline were randomised and had either gabapentin (25 to 35 mg/kg/day) or placebo added to their baseline antiepileptic drugs. The primary analysis of RRatio (Modified Intent To Treat (MITT) population) demonstrated that gabapentin was significantly better than placebo in controlling partial seizures (p = 0.04). Results for the Intent To Treat (ITT) population did not show a significant difference in RRatio between the treatment groups. Further analysis using rank-transformed data was performed as the data showed evidence of non-normality of distribution. Results of this analysis showed that mean RRatio was significantly lower (better) for the gabapentin treatment group than for the placebo group in both the MITT (p = 0.01) and ITT (p = 0.03) populations.

Neuropathic pain.

Adults.

The efficacy and safety of gabapentin for the treatment of neuropathic pain in adults over 18 years of age were assessed in two randomised, double-blind, parallel-group, placebo-controlled, multi-centre studies. One study examined the efficacy and safety of gabapentin in the treatment of painful diabetic peripheral neuropathy and the other study was conducted in patients with post-herpetic neuralgia. The studies were of a similar design. Following a baseline screening week and randomisation, gabapentin was titrated from 900 mg/day to 1800 mg/day, 2400 mg/day and 3600 mg/day divided into three times a day dosing consecutively over the first four weeks of the study. Patients were then maintained at the maximum dose that was tolerated for the remaining four weeks. The primary efficacy measure used in both studies was change from baseline to the final week in mean pain score obtained from daily pain diaries (pain was measured using an 11-point Likert scale). Several secondary outcomes were also assessed including: the Short-Form McGill Pain Questionnaire (SF-MPQ) (sensory, affective and total pain scores); SF-MPQ visual analogue scale (VAS) and present pain intensity scale (PPI); mean sleep interference score; Patient and Clinical Global Impression of Change (PGIC and CGIC) and the quality of life measures SF-36 Quality of Life Questionnaire (QOL) and Profile of Mood States (POMS).
Results from both studies demonstrated that gabapentin provided statistically significantly greater improvement in relief of neuropathic pain than placebo. In patients with painful diabetic peripheral neuropathy, mean pain score decreased by 2.6 in patients receiving gabapentin and 1.4 in patients receiving placebo (p < 0.001). In the post-herpetic neuralgia study, mean pain score decreased by 2.1 in patients receiving gabapentin and 0.5 in patients receiving placebo (p < 0.001). Gabapentin was significantly better than placebo in controlling pain from week two of both studies (p < 0.001). Sleep interference scores, Short-Form McGill sensory, affective and total pain scores, VAS and PPI scale as well as PGIC, CGIC and some of the quality of life measures showed significant differences in favour of gabapentin.

5.2 Pharmacokinetic Properties

All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolised in humans.

Absorption.

Gabapentin bioavailability is not dose proportional; i.e. as dose is increased, bioavailability decreases. A 400 mg dose, for example, is about 25% less bioavailable than a 100 mg dose. Over the recommended dose range of 300 to 600 mg three times a day, however, the differences in bioavailability are not large and bioavailability is about 60%. The bioavailability of the 800 mg dose was found to be approximately 35% in single and multiple dose studies. The absolute bioavailability of gabapentin following daily doses of 1200, 2400, 3600 and 4800 mg/day averaged 47%, 34%, 33% and 27% respectively. Food has no effect on the rate and extent of absorption of gabapentin.

Distribution.

Gabapentin circulates largely unbound (< 3%) to plasma proteins. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58 ± 6 L (Mean ± SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.

Metabolism and excretion.

Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolised in humans.
The elimination half-life of gabapentin is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed by haemodialysis.
Dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended (see Section 4.2 Dose and Method of Administration).

Special populations.

Patients with renal insufficiency.

Subjects with renal insufficiency (mean creatinine clearance ranging from 13 mL/min to 114 mL/min) were administered 400 mg oral dose of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance (CLcr) > 60 mL/min) to 52 hours (CLcr < 30 mL/min) and gabapentin renal clearance ranged from about 90 mL/min (CLcr > 60 mL/min) to about 10 mL/min (CLcr < 30 mL/min). Gabapentin dosage should be adjusted in patients with compromised renal function (see Section 4.2 Dose and Method of Administration).

Patients on haemodialysis.

In a study in anuric patients, the elimination half-life of gabapentin on non-dialysis days was about 132 hours; dialysis three times a week (4 hour duration) lowered the apparent half-life of gabapentin by about 60%, from 132 hours to 51 hours. Gabapentin dosage should be adjusted in patients undergoing haemodialysis (see Section 4.2 Dose and Method of Administration).

Elderly (≥ 65 years).

In a study examining the effect of age on the elimination of gabapentin, apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those younger than 30 years of age to about 125 mL/min in those older than 70 years of age. Renal clearance also declined with age; however, the decline in the renal clearance of gabapentin can largely be explained by the decline in renal function. Reduction of gabapentin dose may be required in patients who have age-related compromised renal function.

Children and adolescents.

Gabapentin pharmacokinetics were determined in 24 healthy paediatric subjects between the ages of 4 and 12 years. In general, gabapentin plasma concentrations in these children are similar to those in adults.

5.3 Preclinical Safety Data

Genotoxicity.

There is no evidence that gabapentin has genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. Gabapentin did not induce structural chromosome aberrations in mammalian cells in vitro or in vivo and did not induce micronucleus formation in the bone marrow of hamsters.

Carcinogenicity.

Gabapentin was given in the diet to mice at 200, 600 and 2000 mg/kg/day and to rats at 250, 1000 and 2000 mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell adenoma and carcinoma was found only in male rats at the highest dose. Peak plasma medicine concentrations and areas under the concentration time curve in rats at 2000 mg/kg/day were 14 times higher than plasma concentrations in humans given the recommended maximum tolerated dose of 2400 mg/day. The pancreatic acinar cell tumours in male rats were low grade malignancies, which did not metastasise or invade surrounding tissue and were similar to those seen in concurrent controls. The relevance of these pancreatic acinar cell tumours in male rats to carcinogenic risk in human is unclear.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, purified talc, maize starch, gelatin, sodium lauryl sulfate, purified water, titanium dioxide, iron oxide red [400 mg], iron oxide yellow [300 mg, 400 mg].

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, the information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.