Consumer medicine information

Gapentin Capsules

Gabapentin

BRAND INFORMATION

Brand name

Gapentin Capsules

Active ingredient

Gabapentin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Gapentin Capsules.

SUMMARY CMI

GAPENTIN capsules

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before taking this medicine.

1. Why am I taking GAPENTIN?

GAPENTIN capsules contains the active ingredient gabapentin. GAPENTIN is used to control epilepsy and treat neuropathic pain. For more information, see Section 1. Why am I taking GAPENTIN? in the full CMI.

2. What should I know before I take GAPENTIN?

Do not take if you have ever had an allergic reaction to gabapentin or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take GAPENTIN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with GAPENTIN and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take GAPENTIN?

  • Your doctor will tell you how many GAPENTIN capsules you need to take each day. This may depend on your age, your condition and whether or not you are taking any other medicines.
  • Swallow GAPENTIN whole with a full glass of water.

More instructions can be found in Section 4. How do I take GAPENTIN? in the full CMI.

5. What should I know while taking GAPENTIN?

Things you should do
  • Remind any doctor, dentist or pharmacist, surgeon, or anaesthetist you visit that you are taking GAPENTIN.
  • Tell your doctor immediately if you have any thoughts of suicide or self-harm, any unusual changes in mood or behaviour, or show signs of depression.
Things you should not do
  • Do not stop taking GAPENTIN or lower the dose without checking with your doctor.
Driving or using machines
  • Do not drive, operate machinery, ride a bike as GAPENTIN may cause drowsiness, dizziness, lightheadedness or sleepiness in some people.
Drinking alcohol
  • Avoid alcohol as it can make you more sleepy, dizzy or light-headed.
Looking after your medicine
  • Keep your capsules in a cool dry place where the temperature stays below 25°C

For more information, see Section 5. What should I know while taking GAPENTIN? in the full CMI.

6. Are there any side effects?

Common side effects include dizziness, light-headedness, headache, sleeplessness, feeling tired, drowsy, unfriendliness, unusually overactive, forgetfulness, loss of concentration, confusion, difficulty speaking, weight change, constipation, diarrhoea, nausea, vomiting, indigestion, dry mouth, red swollen gums, muscle pain, cramps, back pain, swelling hand or feet, runny or blocked nose, fever, bronchitis, lung infection, sore throat, coughing. Serious side effects include unusual changes in mood or behaviour, increased irritability or agitation, depression, seeing or hearing things that are not there, blurred or double vision, uncontrollable jerky eye movements, difficulty seeing, fever, severe chills, sore throat or mouth ulcers, trouble breathing, loss of consciousness, severe seizures, chest pain, fast heart rate, sudden signs of allergy, severe skin rash, high body temperature enlarged lymph nodes For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: Before taking GAPENTIN, tell your doctor if you have a history of drug abuse. GAPENTIN poses risks of abuse and dependence. Taking GAPENTIN 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. If you have any concern about taking this medicine, speak to your doctor.



FULL CMI

GAPENTIN capsules

Active ingredient(s): gabapentin

Consumer Medicine Information (CMI)

This leaflet provides important information about taking GAPENTIN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking GAPENTIN.

Where to find information in this leaflet:

1. Why am I taking GAPENTIN?
2. What should I know before I take GAPENTIN?
3. What if I am taking other medicines?
4. How do I take GAPENTIN?
5. What should I know while taking GAPENTIN?
6. Are there any side effects?
7. Product details

1. Why am I taking GAPENTIN?

GAPENTIN contains the active ingredient gabapentin.

GAPENTIN belongs to a group of medicines called anticonvulsants.

GAPENTIN is used to control epilepsy. Epilepsy is a condition where you have repeated seizures (fits). There are many different types of seizures, ranging from mild to severe.

GAPENTIN is also used to treat neuropathic pain, type of pain caused by damage to the nerves.

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

GAPENTIN also has pain relieving effects.

Your doctor may have prescribed GAPENTIN in addition to other medicines that you may be taking. This may be necessary if your current treatment is no longer working as well.

Your doctor may have prescribed GAPENTIN for another reason.

GAPENTIN may lead to dependence on this medicine.

Ask your doctor if you have any questions about why GAPENTIN has been prescribed for you.

Use in children

There is not enough information to recommend the use of this medicine in children:

  • under the age of 3 years to control epilepsy, or
  • under the age of 18 years to treat neuropathic pain

2. What should I know before I take GAPENTIN?

Warnings

When you must not take GAPENTIN

Do not take GAPENTIN if:

  • you are allergic to gabapentin, or any of the ingredients listed at the end of this leaflet. Some of the 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.
  • Always check the ingredients to make sure you can take this medicine.
  • the expiry date printed on the pack has passed or if the packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • have allergies to any other medicines, especially barbiturates or any other anticonvulsant medicines or any other substances, such as foods, preservatives or dyes.
  • have any other medical conditions:
    - kidney problems
    - mixed seizure disorders that include absence seizures.
  • take any medicines for any other condition
  • have a history of drug abuse and/or psychiatric disorders.
    - GAPENTIN poses risks of abuse and dependence. Your body may become used to you taking GAPENTIN and this may result in physical dependence. It means that you may experience withdrawal symptoms if you stop taking GAPENTIN suddenly. So it is important to strictly follow the directions given by your doctor.
  • are pregnant or plan to become pregnant.
  • are breast-feeding or plan to breast-feed.
  • if you notice any of the symptoms related to these serious skin reactions described in section 6 under table titled "Serious side effects", stop taking gabapentin and seek medical attention immediately.
    - Serious skin rashes including Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with gabapentin.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Pregnancy

Check with your doctor if you are pregnant or intend to become pregnant.

If you are pregnant or think you may be pregnant, you must tell your doctor straight away and discuss possible risks the medicine you are taking might pose to your unborn baby.

If you are planning to become pregnant you should discuss your treatment with your doctor as early as possible before you become pregnant. Effective contraception must be used by women of childbearing potential.

GAPENTIN should not be taken during pregnancy, unless you are told otherwise by your doctor. GAPENTIN may affect your developing baby if you take it during pregnancy. Some medicines used to treat epilepsy have reported an increased risk of harm to the developing baby.

You should not stop your treatment without discussing this with your doctor.

Do not suddenly discontinue taking this medicine. If taken during pregnancy, gabapentin may lead to withdrawal symptoms in newborn infants. This risk might be increased when gabapentin is taken together with opioid analgesics (medicines for treatment of severe pain).

It is also very important to control your fits while you are pregnant. If it is necessary for you to take GAPENTIN, your doctor can help you decide whether or not to take it during pregnancy.

Breastfeeding

Gabapentin, the active substance of GAPENTIN, is passed on through milk. Because the effect on the baby is unknown, tell your doctor if you are breastfeeding or intend to breastfeed.

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 GAPENTIN.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with GAPENTIN and affect how it works.

Some medicines be affected by GAPENTIN 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.

GAPENTIN and certain other medicines may influence each other.

Taking GAPENTIN 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
  • antacids, medicines used to treat heartburn or reflux
  • opioids, medicines used to treat severe pain e.g. morphine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect GAPENTIN. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking GAPENTIN.

4. How do I take GAPENTIN?

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack ask your doctor or pharmacist for help.

How much to take

  • Your doctor will tell you how many capsules you need to take each day. This may depend on your age, your condition and whether or not you are taking any other medicines.
  • Your doctor may recommend that you start with a low dose of GAPENTIN and slowly increase the dose to the lowest amount needed to control your epilepsy/convulsions or neuropathic pain.
  • Follow the instructions provided and take GAPENTIN until your doctor tells you to stop.

How to take GAPENTIN

  • Swallow GAPENTIN whole with a full glass of water.

When to take GAPENTIN

  • GAPENTIN should be used at about the same time each day.
  • Taking GAPENTIN at the same time each day will have the best effect. It will also help you remember when to take the capsules.
  • If you are taking GAPENTIN three times a day, do not allow more than 12 hours between doses.
  • It does not matter if you take GAPENTIN before or after food.

How long to take GAPENTIN

  • Continue taking your medicine for as long as your doctor tells you to.
  • GAPENTIN helps control your condition but does not cure it. Therefore, you must take your medicine every day, even if you feel well.
  • Do not stop taking GAPENTIN, or lower the dose, without checking with your doctor. Do not let yourself run out of medicine over the weekend or holidays.
  • Stopping GAPENTIN suddenly may worsen your condition or increase your chance of experiencing withdrawal symptoms, such as anxiety, difficulty sleeping, feeling sick (nausea), pain, excessive sweating, shaking, headache, depression, feeling abnormal, dizziness, feeling generally unwell, and diarrhoea (runny stools). These effects usually occur within 48 hours after sopping GAPENTIN. If you experience withdrawal effects, you should contact your doctor. If you want to stop taking GAPENTIN, discuss with your doctor first. They will tell you how to do this. If appropriate, your doctor will slowly reduce your dose before you can stop taking it completely.

If you forget to take GAPENTIN

GAPENTIN should be taken regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then go back to taking GAPENTIN as you would normally.

Otherwise 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.

Do not take a double dose to make up for the dose you missed.

  • This may increase the chance of you getting an unwanted side effect.

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

If you have trouble remembering to take GAPENTIN, ask your pharmacist for help.

If you take too much GAPENTIN

If you think that you have used too much GAPENTIN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Symptoms of an overdose may include you falling unconscious feeling drowsy, weak, unsteady when walking, having double vision, slurred speech or diarrhoea.

5. What should I know while taking GAPENTIN?

Things you must do

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

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

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

If you feel GAPENTIN is not helping your condition, tell your doctor. Your doctor may need to change your medicine.

If, for any reason, you have not taken GAPENTIN exactly as prescribed, tell your doctor. Otherwise, your doctor may change your treatment unnecessarily.

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

Call your doctor straight away if:

  • you have any thoughts of suicide or self-harm, any unusual changes in mood or behaviour, or show signs of depression.
    Some people being treated with anti-epileptics, such as GAPENTIN, have had thoughts of harming or killing themselves.
    Patients and caregivers should be alert and monitor for signs and symptoms of suicide, these include:
    - 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.
    Any mention of suicide or violence must be taken seriously.
  • you or someone you know is demonstrating these warning signs and symptoms of suicide while taking GAPENTIN, contact your doctor or a mental health professional right away.
  • you become pregnant while taking GAPENTIN.

Remind any doctor, dentist or pharmacist, surgeon you visit that you are taking GAPENTIN if you are going to have any surgery or procedure (including dental surgery).

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 take GAPENTIN to treat any other complaints unless your doctor tells you to.
  • Do not give GAPENTIN to anyone else, even if their symptoms seem similar to yours or they have the same condition as you.
  • Do not stop taking GAPENTIN or lower the dose without checking with your doctor.

Stopping GAPENTIN suddenly, if you have epilepsy, may cause unwanted side effects or make your condition worse. Your doctor will slowly reduce your dose before you can stop taking it completely.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how GAPENTIN affects you.

As with other anticonvulsant medicines, GAPENTIN may cause drowsiness, dizziness, light-headedness or sleepiness in some people. Make sure you know how you react to GAPENTIN 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.

Drinking alcohol

Tell your doctor if you drink alcohol.

Be careful when drinking alcohol while you are taking GAPENTIN.

Combining GAPENTIN and alcohol can make you more sleepy, dizzy or light-headed. Your doctor may suggest you avoid alcohol while you are being treated with GAPENTIN.

Looking after your medicine

  • Store below 25°C.
  • Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack, they may not keep well.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to take this medicine, your doctor or pharmacist tells you to stop taking, it is out of date or damaged, take it to any pharmacy for safe disposal.

Do not take this medicine after the expiry date.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking GAPENTIN.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

It can be difficult to tell whether side effects are the result of taking GAPENTIN; 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.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

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

Less serious side effects

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

Less serious side effectsWhat to do
  • dizziness* or light-headedness
  • headache
  • sleeplessness
  • feeling tired or drowsy*
  • unfriendliness*
  • unusually overactive*
  • 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 of feet
  • runny or blocked nose
  • fever*
  • bronchitis*, lung infection*
  • sore throat and discomfort when swallowing, coughing.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • weakness, unsteadiness when walking including falling, reduced co-ordination or slowed reactions (tremor)
  • 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
Tell your doctor as soon as possible and seek medical attention immediately if you notice any of the serious side effects.
  • reddish non-elevated, target-like or circular patches on the trunk, often with central blisters, skin peeling, ulcers of mouth, throat, nose, genitals and eyes.
    These serious skin rashes can be preceded by fever and flulike symptoms (Stevens-Johnson syndrome, toxic epidermal necrolysis).
  • widespread rash, high body temperature and enlarged lymph nodes (DRESS syndrome or drug hypersensitivity syndrome).
Stop taking GAPENTIN and seek medical attention immediately if you notice any of the serious skin rashes symptoms occurred.

The side effects in the above lists marked * have been specifically reported in children taking GAPENTIN.

Very Serious side effects

Serious side effectsWhat to do
  • 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.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
This list includes very serious side effects. You may need urgent medical attention of hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

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 side effects. You may not experience any of them.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What GAPENTIN contains

Active ingredient
(main ingredient)		GAPENTIN capsules contain either 100 mg, 300 mg and 400 mg of gabapentin.
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • purified talc
  • maize starch
  • gelatin
  • titanium dioxide
  • iron oxide yellow (300 mg and 400 mg capsules only)
  • iron oxide red (400 mg capsule only)
  • TekPrint SB-6018 Blue ink
Potential allergensContains sugars as lactose.

Do not take this medicine if you are allergic to any of these ingredients.

What GAPENTIN capsule looks like

GAPENTIN 100 mg capsules - white capsule printed with “G 100” in blue ink containing a white crystalline powder. (AUST R 107472).

GAPENTIN 300 mg capsules - yellow capsule printed with “G 300” in blue ink containing a white crystalline powder. (AUST R 107494).

GAPENTIN 400 mg capsules - orange capsule printed with “G 400” in blue ink containing a white crystalline powder. (AUST R 107498).

Who distributes GAPENTIN capsules

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne
VIC, 3121
www.arrotex.com.au

This leaflet was prepared in August 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Gapentin Capsules

Active ingredient

Gabapentin

Schedule

S4

 

1 Name of Medicine

Gabapentin.

2 Qualitative and Quantitative Composition

Gapentin 100 mg capsules contain 100 mg of gabapentin.
Gapentin 300 mg capsules contain 300 mg of gabapentin.
Gapentin 400 mg capsules contain 400 mg of gabapentin.

Excipients with known effect.

Gapentin capsules: contains sugar as lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Gapentin 100 mg capsules are size 3 white capsule printed with "G 100" in blue ink containing a white crystalline powder.
Gapentin 300 mg capsules are size 0 yellow capsule printed with "G 300" in blue ink containing a white crystalline powder.
Gapentin 400 mg capsules are size 0 orange capsule printed with "G 400" in blue ink containing a white crystalline powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Gapentin 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 anti-epileptic medicines.
Gapentin 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 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 capsules on Day 1, 300 mg capsules twice a day on Day 2, 300 mg capsules 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 anti-epileptic 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 mg 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 (TID) 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.

Dosage 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 mg to 400 mg is recommended, then 200 mg 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 anti-epileptic 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 is contraindicated in patients who have demonstrated hypersensitivity to gabapentin or 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 not generally 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 opioid 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, coprescription 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 (AED), 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 antiepileptic drugs 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 antiepileptic drug-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 AEDs 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 of 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.

Severe cutaneous adverse reactions (SCARs).

SCARs including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported rarely in association with gabapentin treatment. At the time of prescribing patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, gabapentin should be withdrawn immediately, and an alternative treatment considered (as appropriate).
If the patient has developed a serious reaction such as SJS, TEN or DRESS with the use of gabapentin, treatment with gabapentin must not be restarted at any time.
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 in patients with current or past substance abuse.
Patients should be carefully evaluated for a history of substance abuse and/or psychiatric disorders prior to being prescribed gabapentin and observed for signs of gabapentin abuse or dependence (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. Withdrawal symptoms may occur shortly after discontinuation, usually within 48 hours. Most frequently reported symptoms include anxiety, insomnia, nausea, pains, sweating, tremor, headache, depression, feeling abnormal, dizziness, malaise, 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).

Women of childbearing potential/contraception.

Gabapentin use in the first trimester of pregnancy may cause major birth defects in the unborn child. Gabapentin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential must use effective contraception during treatment (see Section 4.6 Fertility, Pregnancy and Lactation).

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 plan to take during your treatment with gabapentin.
2. No teratogenic effects have been found in animals. However, the risk to the human foetus 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 (see Section 4.6 Fertility, Pregnancy and Lactation).
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, sedation, and death 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 ethinyl estradiol when administered concomitantly with an oral contraceptive containing these two medicines (N=13).

Antacid.

Coadministration 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 D)
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 antiepileptic medicinal product.
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.
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 medicine, taking into account the importance of the medicine 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 this medication 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 premarketing 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 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 summarized 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 medicines 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 age 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 systems.

Coagulation defect.

Nervous system.

Aura disappeared, occipital neuralgia.

Psychobiologic function.

Sleepwalking.

Respiratory system.

Pseudo-croup, hoarseness.

Adults older than 18 years of age with neuropathic pain.

The most commonly observed adverse events reported with the use of gabapentin in adults older than 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, abnormal thinking, vertigo, rash and amblyopia.
Of the 821 adults who received gabapentin in the painful diabetic peripheral neuropathy and post-herpetic neuralgia trial, 13.2% discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were dizziness (4.4%), somnolence (2.9%), ataxia (1.0%) 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, agitation, 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, toxic epidermal necrolysis, 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.
After discontinuation of short-term and long-term treatment with gabapentin, withdrawal symptoms have been observed in some patients. Most frequently reported symptoms include anxiety, insomnia, nausea, pains, sweating, tremor, headache, depression, feeling abnormal, dizziness, and malaise (see Section 4.4 Special Warnings and Precautions for Use).
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 medicine.

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 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 medicine 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 the drug 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 Poisons Information Centre on 13 11 26 (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 medicines 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 GABAA, GABAB, 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 of more antiepileptic medicines at therapeutic levels and were observed on their established antiepileptic medicine 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 (all patients who received any doses of treatment) population in each study, unless otherwise indicated.
One study compared gabapentin 1200 mg/day, given as three divided doses (divided T.I.D.) 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 1200 mg/day gabapentin (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, nontitrated = 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 nontitrated group reporting the higher incidence, however, it did not lead to increased discontinuation in this group.

Paediatric patients.

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, multicentre clinical studies. The studies were conducted in 247 children who had refractory partial seizures and were receiving 1 to 3 standard antiepileptic medicines. 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 AEDs. The primary analysis of RRatio (MITT population) demonstrated that gabapentin was significantly better than placebo in controlling partial seizures (p = 0.04). Results for the 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 older than 18 years of age were assessed in two randomised, double-blind, parallel-group, placebo-controlled, multicentre 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, 2400 mg 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 decreased. A 400 mg dose, for example, is about 25% less bioavailability than a 100 mg dose. Over the recommended dose range of 300 mg 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 mg/day, 2400 mg/day, 3600 mg/day, 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 in those 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-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 nondialysis day 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 over 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 aged-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, plasma gabapentin 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 gabapentin concentrations and areas under the concentration time curve in rats at 2000 mg/kg/day are 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 are 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

Gapentin capsules contain lactose monohydrate, maize starch, purified talc, gelatin, titanium dioxide, iron oxide yellow (300 mg and 400 mg capsules only), iron oxide red (400 mg capsules only) and TekPrint SB-6018 Blue Ink.

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, 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.

6.5 Nature and Contents of Container

Gapentin 100 mg capsules are available in blister pack (PVC/Al) of 100 capsules.
Gapentin 300 mg capsules are available in blister pack (PVC/Al) of 100 capsules.
Gapentin 400 mg capsules are available in blister pack (PVC/Al) of 100 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Gabapentin is a white to off-white crystalline solid. It is freely soluble in water and both basic and acidic aqueous solutions.
The structural formula of gabapentin is shown below:

Chemical structure.


Chemical name: 1-(aminomethyl) cyclohexaneacetic acid.
Molecular formula: C9H17NO2.
Molecular weight: 171.24.

CAS number.

60142-96-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes