Consumer medicine information

Cipla Pregabalin

Pregabalin

BRAND INFORMATION

Brand name

Cipla Pregabalin

Active ingredient

Pregabalin

Schedule

SUMMARY CMI

Cipla Pregabalin

Consumer Medicine Information (CMI) summary

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

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

1. Why am I using Cipla Pregabalin?

Cipla Pregabalin contains the active ingredient, pregabalin. Cipla Pregabalin is taken to treat neuropathic pain, which is pain caused by an abnormality of, or damage to, the nerves. Cipla Pregabalin is also used to control epilepsy which is a condition where you have repeated seizures (fits) For more information, see Section 1. Why am I using Cipla Pregabalin? in the full CMI.

2. What should I know before I use Cipla Pregabalin?

Do not use if you have ever had an allergic reaction to pregabalin 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 (including benzodiazepines and opioids), or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Cipla Pregabalin? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Cipla Pregabalin 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 use Cipla Pregabalin?

Cipla Pregabalin should be administered once daily after an evening meal. It should be swallowed whole and should not be split, crushed or chewed. More instructions can be found in Section 4. How do I use Cipla Pregabalin? in the full CMI.

5. What should I know while using Cipla Pregabalin?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Cipla Pregabalin. If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. Tell your doctor immediately if you experience any changes in your vision, trouble breathing or shallow breaths. 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 take Cipla Pregabalin to treat any other complaints unless your doctor tells you to. Do not stop taking your medicine or lower the dosage without checking with your doctor.
Driving or using machines	Be careful driving or operating machinery until you know how Cipla Pregabalin affects you.
Drinking alcohol	Be careful when drinking alcohol while you are taking this medicine.
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 using Cipla Pregabalin? in the full CMI.

6. Are there any side effects?

Tell your doctor or pharmacist if you notice any of the following less serious side effects and they worry you: dizziness, feeling tired or drowsy, constipation, diarrhoea, nausea, headache, increase in weight, unsteadiness when walking, reduced coordination, shaking or tremors, dry mouth, blurred or double vision. Tell your doctor as soon as possible if you notice any of the following more serious side effects: unusual changes in mood or behaviour, signs of new or increased irritability or agitation, signs of depression, confusion, swelling of the hands, ankles or feet, enlargement of breasts, unexplained muscle pain, tenderness and weakness, passing little to no urine, trouble breathing, shallow breath. 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 Cipla Pregabalin, tell your doctor if you have a history of drug abuse. Pregabalin poses risks of misuse, abuse and dependence. Using Cipla Pregabalin 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

Cipla Pregabalin

Active ingredient(s): Pregabalin

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Cipla Pregabalin?

Cipla Pregabalin contains the active ingredient, pregabalin.

Cipla Pregabalin belongs to a group of medicines called anticonvulsants. These medicines are thought to work by controlling brain chemicals which send signals to nerves so that seizures do not happen. Cipla Pregabalin also has pain relieving effects.

Cipla Pregabalin is used to treat neuropathic pain, which is pain caused by an abnormality of, or damage to, the nerves.

Cipla Pregabalin is also 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.

Cipla Pregabalin may be used alone, or in combination with other medicines, to treat your condition.

Your doctor may prescribe Cipla Pregabalin in addition to your current therapy when your current treatment is no longer working as well as before.

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

Your doctor may have prescribed it for another reason.

2. What should I know before I use Cipla Pregabalin?

Warnings

Do not use Cipla Pregabalin if:

you are allergic to pregabalin, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
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.

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 such as:
- congestive heart failure,
- hereditary problems with galactose metabolism
- kidney problems,
- diabetes,
- Depression.
have a history of drug abuse.

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

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

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

Cipla Pregabalin is not recommended for use during pregnancy. However, if you have epilepsy, it is very important to control your fits while you are pregnant. If it is necessary for you to take Cipla Pregabalin, your doctor can help you decide whether or not to take it during pregnancy.

Pregabalin use during the first 3 months of pregnancy may cause birth defects in the unborn child that require medical treatment. In a study reviewing data from women in Nordic countries who took pregabalin in the first 3 months of pregnancy, 6 babies in every 100 had such birth defects. This compares to 4 babies in every 100 born to women not treated with pregabalin in the study.

Abnormalities of the face (orofacial clefts), the eyes, the nervous system (including the brain), kidneys and genitals have been reported.

Effective contraception must be used by women of childbearing potential.

Tell your doctor if you are breastfeeding or intend to breastfeed.

The active ingredient in Cipla Pregabalin passes into breast milk and its safety in infants is unknown. It is recommended that you do not breast-feed while taking Cipla Pregabalin.

Use in Children.

There is not enough information to recommend the use of this medicine in children under the age of 18 years.

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 be affected by Cipla Pregabalin 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 will advise you. Using Cipla Pregabalin 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 minimize the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Cipla Pregabalin.

4. How do I use Cipla Pregabalin?

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

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

How much to take

Your doctor will tell you how much Cipla Pregabalin to take. 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 Cipla Pregabalin and slowly increase the dose to the lowest amount needed to control your epilepsy/convulsions or neuropathic pain.
The usual dose range is 150 mg per day to 600 mg per day given in two divided doses.

When to take Cipla Pregabalin

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take Cipla Pregabalin

Continue taking your medicine for as long as your doctor tells you.
This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.
Do not stop taking Cipla Pregabalin, or lower the dosage, without checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays.
Stopping Cipla Pregabalin suddenly may worsen your condition or increase your chance 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 use Cipla Pregabalin

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 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 your medicine, ask your pharmacist for some hints.

If you use too much Cipla Pregabalin

If you think that you or anyone else may have used too much Cipla Pregabalin, urgent medical attention may be needed.

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.

Symptoms of an overdose with Cipla Pregabalin may include mood changes, feeling tired, confusion, depression, agitation, restlessness or seizures.

5. What should I know while using Cipla Pregabalin?

Things you should do

If you are about to be started on any new medicine remind any doctor, dentist or pharmacist you visit that you are using Cipla Pregabalin.
Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.
If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

Tell your doctor if you feel Cipla Pregabalin is not helping your condition.
Your doctor may need to change your medicine.
Tell your doctor if, for any reason, you have not taken Cipla Pregabalin exactly as prescribed.
Otherwise, your doctor may change your treatment unnecessarily.
Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Call your doctor straight away if you:

experience any changes in your vision: Cipla Pregabalin may cause blurring or other changes in eyesight. Your doctor may ask you to stop taking Cipla Pregabalin to improve these symptoms.
have any thoughts of suicide or self-harm, any unusual changes in mood or behaviour, or show signs of depression. Some people taking medicines to treat convulsions, such as Cipla Pregabalin, have had thoughts of harming themselves or taking their life.

Patients and caregivers should be alert and monitor for these effects. Signs and symptoms of suicidal risk include:

thoughts or talk of death or suicide
thoughts or talk of self-harm or harm to others o any recent attempts of self-harm
new or an increase in aggressive behaviour, irritability or agitation
new or worsening depression.
Mention of suicide or violence must be taken seriously.

If you or someone you know is demonstrating these warning signs of suicide while taking Cipla Pregabalin, contact your doctor or a mental health professional right away.

experience trouble breathing or shallow breaths.
If you have nervous system or respiratory disorders, kidney problems, or you are older than 65, your doctor may adjust your dose.
become pregnant while taking Cipla Pregabalin

Things you should not do

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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Cipla Pregabalin affects you.
As with other anticonvulsant medicines, Cipla Pregabalin may cause dizziness in some people, with other anticonvulsant medicines. If you have any of these symptoms, do not drive, operate machinery or do not do anything else that could be dangerous

Drinking alcohol

Be careful when drinking alcohol while you are taking this medicine

If you drink alcohol, symptoms such as dizziness and drowsiness may be worse.

Looking after your medicine

Keep your capsules in a cool dry place where the temperature stays below 25°C.

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 children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

Cipla Pregabalin helps most people with neuropathic pain or epilepsy, but it may have unwanted side effects in a few people.

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 Cipla Pregabalin, effects 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.

Do not be alarmed by the list of side effects.

You may not experience any of them.

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

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

Less serious side effects

Less serious side effects

What to do

Nervous system related

dizziness
feeling tired or drowsy
headache
unsteadiness when walking, reduced co-ordination, shaking or tremors

Gastrointestinal related

constipation
diarrhoea
nausea
dry mouth

Metabolism related

increase in weight

Eye related

blurred or double vision.

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

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Psychiatric related;

unusual changes in mood or behaviour
signs of new or increased irritability,or agitation
signs of depression
confusion

Musculoskeletal related

unexplained muscle pain, tenderness and weakness

Respiratory related

trouble breathing, shallow breaths

Other side effects:

passing little to no urine
swelling of the hands, ankles or feet
enlargement of breasts

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.

More serious side effects

More serious side effects

What to do

Respiratory related:

shortness of breath

Eye related

irritated red eyes that are sensitive to light

Neurological related:

more frequent or more severe seizures (fits)

Allergy related:

rash, itching or hives
reddish non-elevated, target-like or circular patches on the trunk, often with central blisters
skin peeling
swelling of the face, lips, tongue or other parts of the body
shortness of breath, wheezing or difficulty breathing

Skin related

serious skin reactions characterized by 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 flu-like symptoms (Stevens-Johnson syndrome, toxic epidermal necrolysis)

Other side effects:

swelling of the feet and legs
weight increase due to fluid build-up
ulcers of mouth, throat, nose, genitals and eyes

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

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.

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 blood pressure) can only be found when your doctor does tests from time to time to check your progress.

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 Cipla Pregabalin contains

Active ingredient
(main ingredient)

Pregabalin

Other ingredients
(inactive ingredients)

Starch, Talc
The capsule shells (cap and body) contain:
25 mg, 50 mg, 75 mg, 100 mg, 150 mg 200 mg, 225 mg and 300 mg capsule
Gelatin,
Sodium lauryl sulphate,
Titanium dioxide.
75 mg, 100 mg, 200 mg, 225 mg, 300 mg capsule
FD&C Blue 1,
FD&C Red 40,
FD&C Yellow 6.
Printing ink contains:
Black iron oxide,
Butyl alcohol,
Dehydrated alcohol,
Isopropyl alcohol,
Potassium hydroxide,
Propylene glycol,
Shellac,
Strong ammonia solution.

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

What Cipla Pregabalin looks like

25 mg - white to off white powder filled in size ‘4’ hard gelatin white opaque and white opaque capsule linear printed in black ink with 'Cipla 25 mg' on the cap and ‘677’ on the body.

50 mg - white to off white powder filled in size ‘3’ hard gelatin white opaque and white opaque capsule linear printed in black ink with 'Cipla 50 mg' on the cap and ‘678’ on the body.

75 mg - white to off white powder filled in size ‘4’ hard gelatin orange opaque and white opaque capsule linear printed in black ink with 'Cipla 75 mg' on the cap and ‘679’ on the body.

100 mg - white to off white powder filled in size ‘3’ hard gelatin orange opaque and orange opaque capsule linear printed in black ink with 'Cipla 100 mg' on the cap and ‘681’ on the body.

150 mg - white to off white powder filled in size ‘2’ hard gelatin white opaque and white opaque capsule linear printed in black ink with 'Cipla 150 mg' on the cap and ‘682’ on the body.

200 mg - white to off white powder filled in size ‘1’ hard gelatin light orange opaque and light orange opaque capsule linear printed in black ink with 'Cipla 200 mg' on the cap and ‘683’ on the body.

225 mg - white to off white powder filled in size ‘1’ hard gelatin light orange opaque and white opaque capsule linear printed in black ink with 'Cipla 225 mg' on the cap and ‘684’ on the body.

300 mg - white to off white powder filled in size ‘0’ hard gelatin orange opaque and white opaque capsule linear printed in black ink with 'Cipla 300 mg' on the cap and ‘685’ on the body.

Each blister pack contains 10's, 14's and 56 capsules and in HDPE container with child-resistant cap for 30's and 90's capsules or in HDPE container with screw cap for 500's capsules.

Pack size of 90's and 500's capsules are for dispensing use only.

Blister pack-

AUST R 317646, AUST R 317664,

AUST R 317666, AUST R 317671,

AUST R 317673, AUST R 317677,

AUST R 317679, AUST R 317681

Bottle pack

AUST R 317663, AUST R 317665,

AUST R 317667, AUST R 317672,

AUST R 317674, AUST R 317678,

AUST R 317680, AUST R 317682

Who distributes Cipla Pregabalin

Cipla Australia Pty Ltd

Level 1, 132-136 Albert Road South Melbourne Vic 3205
[email protected]
Phone: 1800-569-074

This leaflet was prepared in January 2024.

Published by MIMS May 2024

BRAND INFORMATION

Brand name

Cipla Pregabalin

Active ingredient

Pregabalin

Schedule

1 Name of Medicine

Pregabalin.

2 Qualitative and Quantitative Composition

Cipla Pregabalin 25 mg hard gelatin capsules: Each hard capsule contains 25 mg of pregabalin.
Cipla Pregabalin 50 mg hard gelatin capsules: Each hard capsule contains 50 mg of pregabalin.
Cipla Pregabalin 75 mg hard gelatin capsules: Each hard capsule contains 75 mg of pregabalin.
Cipla Pregabalin 100 mg hard gelatin capsules: Each hard capsule contains 100 mg of pregabalin.
Cipla Pregabalin 150 mg hard gelatin capsules: Each hard capsule contains 150 mg of pregabalin.
Cipla Pregabalin 200 mg hard gelatin capsules: Each hard capsule contains 200 mg of pregabalin.
Cipla Pregabalin 225 mg hard gelatin capsules: Each hard capsule contains 225 mg of pregabalin.
Cipla Pregabalin 300 mg hard gelatin capsules: Each hard capsule contains 300 mg of pregabalin.
For the full list of excipients, see Section 6.1 List of Excipients.

Description.

Pregabalin is a white to off-white solid, crystalline solid. It is sparingly soluble in water and basic and acidic aqueous solutions.

3 Pharmaceutical Form

Hard capsules.

Cipla Pregabalin 25 mg capsules.

White to off white powder filled in size '4' hard gelatin white opaque and white opaque capsule linear printed in black ink with 'Cipla 25 mg' on the cap and '677' on the body.

Cipla Pregabalin 50 mg capsules.

White to off white powder filled in size '3' hard gelatin white opaque and white opaque capsule linear printed in black ink with 'Cipla 50 mg' on the cap and '678' on the body.

Cipla Pregabalin 75 mg capsules.

White to off white powder filled in size '4' hard gelatin orange opaque and white opaque capsule linear printed in black ink with 'Cipla 75 mg' on the cap and '679' on the body.

Cipla Pregabalin 100 mg capsules.

White to off white powder filled in size '3' hard gelatin orange opaque and orange opaque capsule linear printed in black ink with 'Cipla 100 mg' on the cap and '681' on the body.

Cipla Pregabalin 150 mg capsules.

White to off white powder filled in size '2' hard gelatin white opaque and white opaque capsule linear printed in black ink with 'Cipla 150 mg' on the cap and '682' on the body.

Cipla Pregabalin 200 mg capsules.

White to off white powder filled in size '1' hard gelatin light orange opaque and light orange opaque capsule linear printed in black ink with 'Cipla 200 mg' on the cap and '683' on the body.

Cipla Pregabalin 225 mg capsules.

White to off white powder filled in size '1' hard gelatin light orange opaque and white opaque capsule linear printed in black ink with 'Cipla 225 mg' on the cap and '684' on the body.

Cipla Pregabalin 300 mg capsules.

White to off white powder filled in size '0' hard gelatin orange opaque and white opaque capsule linear printed in black ink with 'Cipla 300 mg' on the cap and '685' on the body.

4 Clinical Particulars

4.1 Therapeutic Indications

Cipla Pregabalin (pregabalin) is indicated for the treatment of neuropathic pain in adults.
Cipla Pregabalin (pregabalin) is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.

4.2 Dose and Method of Administration

Dosage.

The dose range is 150 to 600 mg per day given in two divided doses.

Neuropathic pain.

Cipla Pregabalin treatment can be started at a dose of 150 mg per day, given as two divided doses. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day, given as two divided doses, after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval.
Since diabetes is frequently complicated by renal disease, patients with diabetic neuropathy, in accordance with current clinical practice, should be assessed for renal impairment prior to commencing Cipla Pregabalin and dosage adjusted appropriately.
The effectiveness of pregabalin in the treatment of neuropathic pain has not been assessed in controlled clinical trials for treatment periods longer than 12 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The risks and benefits of treatment to an individual patient should be assessed before extending therapy for longer than 12 weeks.

Epilepsy.

Cipla Pregabalin treatment can be started with a dose of 150 mg per day given as two divided doses. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day given as two divided doses after 1 week. The maximum dosage of 600 mg per day given as two divided doses may be achieved after an additional week.
It is not necessary to monitor plasma pregabalin concentrations to optimise Cipla Pregabalin therapy. Pregabalin does not alter the plasma concentrations of other commonly used anti-convulsant drugs. Similarly, commonly used anti-convulsant drugs do not alter plasma concentrations of pregabalin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Discontinuation of Cipla Pregabalin.

In accordance with current clinical practice, if Cipla Pregabalin has to be discontinued, it is recommended to withdraw it gradually over a minimum of one week (see Section 4.4 Special Warnings and Precautions for Use, Discontinuation).

Dosage adjustment.

Renal impairment.

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. As pregabalin clearance is directly proportional to creatinine clearance (see Section 5.2 Pharmacokinetic Properties, Excretion), dosage reduction in patients with compromised renal function must be individualised according to creatinine clearance (CL_cr), as indicated in Table 1 determined using the following formula (see Equation 1):

Pregabalin is removed effectively from plasma by haemodialysis (50% of drug in 4 hours). For patients receiving haemodialysis, the pregabalin daily dose should be adjusted based on renal function. In addition to the daily dose, a supplementary dose should be given immediately following every 4-hour haemodialysis treatment (see Table 1).

Hepatic impairment.

No dosage adjustment is required for patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Hepatic impairment).

Children and adolescents (< 18 years).

The safety and effectiveness of pregabalin has not been established in patients below the age of 18 years, with either epilepsy or neuropathic pain.

Elderly (> 65 years).

No dosage adjustment is necessary for elderly patients unless their renal function is compromised (see Table 1; see Section 5.2 Pharmacokinetic Properties, Special populations, Elderly (> 65 years)).

Method of administration.

Cipla Pregabalin may be taken with or without food.
Cipla Pregabalin is for oral use only.

4.3 Contraindications

Cipla Pregabalin is contraindicated in patients who have demonstrated hypersensitivity to pregabalin or to any of the excipients listed in Section 6.1.

4.4 Special Warnings and Precautions for Use

Weight gain.

In the controlled studies, weight gain occurred more frequently in patients treated with pregabalin than in patients treated with placebo. Pregabalin associated weight gain was related to dose and length of exposure, but did not appear to be associated with baseline BMI, gender or age.
Some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycaemic medications.

Hypersensitivity reactions.

There have been reports in the post-marketing experience of hypersensitivity reactions, including cases of angioedema. Cipla Pregabalin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.

Severe cutaneous adverse reactions (SCARs).

SCARs including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported rarely in association with pregabalin 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, pregabalin should be withdrawn immediately, and an alternative treatment considered (as appropriate).

Dizziness and somnolence.

Pregabalin causes dizziness and somnolence (see Section 4.8 Adverse Effects (Undesirable Effects)). In the controlled studies, dizziness and somnolence generally began shortly after initiation of pregabalin and occurred more frequently at higher doses. Dizziness and somnolence were the adverse events most frequently leading to withdrawal (4% each) from controlled studies. In pregabalin-treated patients reporting these adverse events in short-term controlled studies, dizziness persisted until the last dose in 31% and somnolence persisted until the last dose in 46%.
There have also been reports of loss of consciousness, confusion, and mental impairment.

Suicidal behaviour and ideation.

Antiepileptic drugs (AED), including pregabalin, 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 randomized 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 pregabalin 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.

Monotherapy for seizure control.

There are insufficient data on seizure control when pregabalin is used as monotherapy once concomitant antiepileptic medical products have been withdrawn in patients where pregabalin was used as add-on therapy.

Misuse, abuse potential or dependence.

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

Renal failure.

Renal failure is a rare adverse reaction to pregabalin. Although the effects of discontinuation on the reversibility of renal failure have not been systematically studied, cases of renal failure have been reported and in some cases discontinuation of pregabalin did show reversibility of this adverse reaction.

Discontinuation.

Withdrawal symptoms have been observed in some patients after discontinuation of pregabalin, including severe symptoms in patients taking high doses. Withdrawal symptoms after discontinuation of both short-term and long-term treatment with pregabalin 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 Cipla Pregabalin).

Congestive heart failure.

There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin. Cipla Pregabalin should be used with caution in these patients.

Blurred vision.

In controlled studies, a higher proportion of patients treated with pregabalin reported blurred vision than did patients treated with placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). In the majority of cases, blurred vision resolved with continued dosing. If blurred vision persists, further assessment should be considered.
Post-marketing experience with pregabalin has reported transient visual blurring and other changes in visual acuity. Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.

Peripheral oedema.

In controlled studies, peripheral oedema occurred more frequently in patients treated with pregabalin than in patients treated with placebo (see Section 4.8 Adverse Effects (Undesirable Effects)).
Peripheral oedema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. There are limited data on the use of pregabalin in patients with congestive heart failure, and pregabalin should be used with caution in these patients.

Creatine kinase elevations.

Treatment with pregabalin was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for pregabalin treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 2% of patients on pregabalin and 1% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three pregabalin treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and pregabalin is not completely understood because the cases had documented factors that may have caused or contributed to these events. Cipla Pregabalin should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.

Concomitant use with opioids.

Concomitant use of opioids may result in severe sedation, respiratory depression, coma, and death. Limit dosages and durations of pregabalin to the minimum required to achieve desired therapeutic effect and monitor patients for signs and symptoms of respiratory depression and sedation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In an observational study of opioid users, those patients who took pregabalin concomitantly with an opioid had an increased risk for opioid-related death compared to opioid use alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19 to 2.36]).

Respiratory depression.

There have been reports of severe respiratory depression in relation to pregabalin use. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly may be at higher risk of experiencing this severe adverse reaction. Dose adjustments may be necessary in these patients (see Section 4.2 Dose and Method of Administration).

Use in the elderly (> 65 years).

Pregabalin treatment has been associated with dizziness and somnolence, which may increase the occurrence of accidental injury (falls) in the elderly population.

Women of childbearing potential/contraception.

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

Paediatric use.

The safety and effectiveness of pregabalin has not been established in patients below the age of 18 years, with either epilepsy or neuropathic pain.

Effects on laboratory tests.

Pregabalin is not known to interfere with any laboratory tests. Some changes in clinical laboratory tests have been noted in patients taking pregabalin (see Section 4.8 Adverse Effects (Undesirable Effects), Table 4 - Investigations).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (< 2% of a dose recovered in urine as metabolites), does not inhibit drug metabolism in vitro, and is not bound to plasma proteins, pregabalin is unlikely to produce, or be subject to, pharmacokinetic interactions.
Accordingly, in in vivo studies no clinically relevant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. In addition, population pharmacokinetic analysis indicated that the three commonly used drug classes, oral antidiabetics, diuretics and insulin, and the commonly used antiepileptic drugs phenytoin, carbamazepine, valproic acid, lamotrigine, phenobarbital, tiagabine and topiramate, had no clinically significant effect on pregabalin clearance. Similarly, these analyses indicated that pregabalin had no clinically significant effect on the clearance of phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate and phenobarbital.
Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinylestradiol does not influence the steady-state pharmacokinetics of either agent.
Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, multiple oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.
In post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking pregabalin 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). There are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g. intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics.
No specific pharmacodynamic interaction studies were conducted in elderly volunteers.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Preclinical data.

In male rats, oral administration of high doses of pregabalin resulted in reversible decreased sperm motility and fertility. These were not observed at exposures (plasma AUC) up to 11 times the expected human exposure at the maximum recommended clinical dose of 600 mg/day. There were also no drug-related effects on sperm parameters in a long term monkey study with exposures up to 8 times the expected maximum human exposure. In female rats, oestrus cycles were prolonged by high oral doses of pregabalin, but fertility was unaffected, and an increase in post-implantation loss also occurred. No adverse effects were seen at an exposure approximately 50 times the expected maximum human exposure.

Human data.

In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 of 46 healthy male subjects were exposed to pregabalin at 600 mg/day for 3 months. Pregabalin did not exhibit detrimental effects on the reproductive function of healthy male subjects, as measured by semen analysis.
(Category D)

Women of childbearing potential/contraception.

Women of childbearing potential have to use effective contraception during treatment (see Section 4.4 Special Warnings and Precautions for Use).
Pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. In a pre- and post-natal study in rats, pregabalin treatment resulted in offspring developmental toxicity at exposures (plasma AUC) ≥ 5 times the expected human exposure at the maximum recommended clinical dose of 600 mg/day. Offspring development was unaffected at 2 times the expected maximum human exposure.

Major congenital malformations.

Data from a Nordic observational study of more than 2700 pregnancies exposed to pregabalin in the first trimester showed a higher prevalence of major congenital malformations (MCM) among the paediatric population (live or stillborn) exposed to pregabalin compared to the unexposed population (5.9% vs. 4.1%).
The risk of MCM among the paediatric population exposed to pregabalin in the first trimester was slightly higher compared to unexposed population (adjusted prevalence ratio and 95% confidence interval: 1.14 (0.96-1.35)), and compared to population exposed to lamotrigine (1.29 (1.01-1.65)) or to duloxetine (1.39 (1.07-1.82)).
The analyses on specific malformations showed higher risks for malformations of the nervous system, the eye, orofacial clefts, urinary malformations and genital malformations, but numbers were small and estimates imprecise.
Pregabalin should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the fetus.

Labour and delivery.

The effects of pregabalin on labour and delivery in pregnant women are unknown. In a pre- and post-natal development study in rats, pregabalin prolonged gestation and induced dystocia at exposures (plasma AUC) approximately 50 times the expected human exposure at the maximum recommended clinical dose of 600 mg/day. These effects were not observed at an exposure that was approximately 12 times the expected human exposure.

Teratogenicity.

Pregabalin was not teratogenic in mice, rats or rabbits. Fetal developmental toxicity was not observed after treatment of pregnant mice and rabbits with oral doses that resulted in respective pregabalin exposures that were 30 times and 17 times the expected human exposure at the maximum recommended clinical dose of 600 mg/day. Increased fetal skeletal variations were seen in rats at oral doses resulting in exposures > 17 times the expected maximum human exposure, but lower doses were not tested in a full study.
Pregabalin is excreted in the milk of lactating women (see Section 5.2 Pharmacokinetic Properties, Breastfeeding women). As the safety of pregabalin in infants is not known, breastfeeding is not recommended in women taking pregabalin. A decision must be made whether to discontinue breastfeeding or to discontinue Cipla Pregabalin therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

Pregabalin may cause dizziness and somnolence and therefore may have an influence on the ability to drive or use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medication affects their ability to perform these activities.

4.8 Adverse Effects (Undesirable Effects)

The pregabalin clinical programme involved over 9000 patients who were exposed to pregabalin, of whom over 5000 were in double-blind placebo-controlled trials. The clinical efficacy program included patients treated for a maximum of 12 weeks duration.
The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 13% for patients receiving pregabalin and 7% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence.
The adverse effects listed may also be associated with the underlying disease and concomitant medications. See Table 3.
Additional adverse reactions reported in a pooled analysis of all pregabalin clinical trials are listed in Table 4 by System Organ Class (SOC). The frequency of these terms have been based on all-causality adverse drug reactions in the clinical trial data set (very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100) and rare (< 1/1000)).

Post-marketing experience.

The following adverse drug reactions were reported during post-marketing surveillance:

Immune system disorders.

Uncommon: Hypersensitivity; Rare: Angioedema, allergic reaction.

Nervous system disorders.

Very common: Headache; Uncommon: Loss of consciousness, mental impairment; Rare: Delirium, parkinsonism.

Cardiac disorders.

Rare: Congestive heart failure.

Eye disorders.

Rare: Keratitis, blindness.

Gastrointestinal disorders.

Common: Nausea, diarrhoea; Rare: Swollen tongue.

General disorders and administration site conditions.

Uncommon: Malaise.

Skin and subcutaneous tissue disorders.

Uncommon: Face swelling, pruritus, alopecia. Rare: Stevens-Johnson syndrome, toxic epidermal necrolysis. Not known: Bullous dermatitis, dermatitis exfoliative.

Renal and urinary disorders.

Rare: Urinary retention.

Reproductive system and breast disorders.

Rare: Gynaecomastia.

Respiratory, thoracic and mediastinal disorders.

Rare: Pulmonary oedema; Not known: Respiratory depression.

Vital signs.

No consistent changes in vital signs have been seen in patients taking pregabalin. Changes in vital signs reported in controlled clinical trials are shown in Table 4.

Elderly (> 65 years).

In a total of 998 elderly patients, no overall differences in safety were observed compared with patients less than 65 years of age.

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.

In overdoses up to 15 g, no unexpected adverse effects were reported.
In post-marketing experience, the most commonly reported adverse events observed when pregabalin was taken in overdose included affective disorder, somnolence, confusional state, depression, agitation and restlessness. Seizures were also reported.

Recommended treatment.

There is no specific antidote for pregabalin. Treatment of Cipla Pregabalin overdose should be symptomatic and supportive.
Consider administration of activated charcoal in the event of a potentially toxic ingestion. Activated charcoal is most effective when administered within one hour of 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.
Haemodialysis may be useful in patients with severe toxicity or those with significant renal impairment (see Section 4.2 Dose and Method of Administration, Renal impairment). Standard haemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours). Emesis is not recommended because of the potential for CNS depression and seizures.
For information on the management of an overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pregabalin is an analogue of the neurotransmitter gamma-aminobutyric acid (GABA). It has analgesic and anticonvulsant activity.
In vitro studies show that pregabalin binds to an auxiliary subunit (α₂-δ protein) of voltage-gated calcium channels in the central nervous system, potently displacing [³H]-gabapentin. Two lines of evidence indicate that binding of pregabalin to the α₂-δ site is required for analgesic and anticonvulsant activity in animal models: (1) Studies with the inactive R-enantiomer and other structural derivatives of pregabalin and (2) Studies of pregabalin in mutant mice with defective drug binding to the α₂-δ protein. In addition, pregabalin reduces the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. The significance of these effects for the clinical pharmacology of pregabalin is not known.
Pregabalin does not show affinity for receptor sites or alter responses associated with the action of several common drugs for treating seizures or pain. Pregabalin does not interact with either GABA_A or GABA_B receptors; it is not converted metabolically into GABA or a GABA agonist; it is not an inhibitor of acute GABA uptake or degradation.
Pregabalin prevents pain-related behaviours in animal models of neuropathic and post-surgical pain, including hyperalgesia and allodynia.
Pregabalin also shows efficacy in animal models of seizures, including maximal electroshock tonic extensor seizures in mice or rats, threshold clonic seizures from pentylenetetrazol, behavioural and electrographic seizures in hippocampal kindled rats, and tonic and clonic seizures in DBA/2 audiogenic mice. Pregabalin does not reduce the incidence of spontaneous absence seizures in Genetic Absence Epilepsy in Rats from Strasbourg (GAERS).

Clinical trials.

Neuropathic pain. The effectiveness of pregabalin for the management of neuropathic pain was investigated in 11 double blind, placebo-controlled, multi-centre studies with either twice a day (BID) or three times a day (TID) dosing.
The analysis of the primary efficacy variable is provided below for each study within the diabetic peripheral neuropathy, and post-herpetic neuralgia population.
The overall picture of the primary efficacy variable across populations is confirmed by the responder rates. The response rates for a 30% reduction in pain score showed that the proportion of patients responding increased with increasing doses, from 34 - 49% at 150 mg per day to 54 - 65% at 600 mg per day, compared with 19 - 45% for placebo. The response rates for a 50% reduction in pain score showed that the proportion of patients responding increased with increasing doses, from 19 - 34% at 150 mg per day to 39 - 50% at 600 mg per day, compared with 8 - 30% for placebo.
Up to 88% of patients treated with 300 or 600 mg/day pregabalin reported benefit, compared with 26 - 66% for placebo, as measured by an improvement in the Patient Global Impressions of Change (PGIC) score. The PGIC is a patient-rated instrument that measures change in a patient's overall status on a scale ranging from 1 (very much improved) to 7 (very much worse).
A significant reduction in pain was seen by Week 1 and maintained relative to placebo throughout the treatment. Significant reductions in sleep interference were seen, when patients were treated with pregabalin for neuropathic pain, by Week 1 and maintained throughout the treatment.

Diabetic peripheral neuropathy (DPN).

The effectiveness of pregabalin for the management of neuropathic pain was investigated in 6 double blind, placebo-controlled, multi-centre studies with either twice a day (BID) or three times a day (TID) dosing. A total of 1525 patients were enrolled in the 6 studies. To enter the study patients had to have moderate to severe pain. The mean age of patients in these studies was 59 years (range 21 - 85 years), 89% of patients had Type II diabetes mellitus with an average HbA1c of 8.9%.
In the 5 completed studies, the average age was 59 years, the duration of diabetes was 11 years, and the average baseline pain score was 6.5. The use of concurrent medication that may affect the assessments was prohibited. Antidiabetic medication was required to be stable and constant during the study. See Table 5.

Post-herpetic neuralgia (PHN).

The effectiveness of pregabalin for the management of neuropathic pain was investigated in 5 double blind, placebo-controlled, multi-centre studies with either twice a day (BID) or three times a day (TID) dosing. A total of 1250 patients were enrolled in the 5 studies. To enter the study patients had to have moderate to severe pain for ≥ 3 months (or ≥ 6 months in one study). The mean duration of PHN for patients in these studies was 3 years (range < 1 - 22 years).
In the 4 completed studies, the average age was 71 years, the average duration of PHN was 38 months, and the average baseline pain score was 6.6. Concomitant use of analgesics and antidepressants was allowed, provided the regimen was stable and in place at the time of randomisation. See Table 6.

Epilepsy. The efficacy of pregabalin as adjunctive therapy was investigated in three 12-week, randomised, double blind, placebo controlled, multi-centre studies involving 1052 patients, with BID and/or TID dosing. Patients had refractory partial seizures with or without secondary generalisation and had mean baseline seizure rates of 21-22 and median baseline seizure rates of 10-12 seizures per 28 days.
The primary efficacy measure in all studies was based on seizure reduction as analysed by response ratio (RRatio), a measure of change defined as [(T - B)/(T + B)] x 100, where B is the patient's baseline seizure frequency and T is the patient's seizure frequency during treatment. The RRatio is distributed within the range -100 to +100. A zero value indicates no change and a complete elimination of seizures would give a value of -100. Responder rate was defined as the proportion of patients who have a ≥ 50% reduction in partial seizure frequency during treatment as compared to baseline. See Table 7.

A significant reduction in seizure frequency was observed by Week 1. Overall, there was a significant reduction in seizure frequency over the 12-week treatment period.
Long-term efficacy data in support of the chronic use of pregabalin for the treatment of patients with partial seizures were provided by four open label extension studies. These studies permitted pregabalin as adjunctive therapy with marketed AEDs. Data from the long-term studies support the long-term use of pregabalin for the treatment of patients with partial seizures, as well as demonstrating the maintenance of effect over the long term.

5.2 Pharmacokinetic Properties

Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy receiving anti-epileptic drugs and patients with chronic pain.

Absorption.

Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within 1 hour following both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥ 90% and is independent of dose. Following repeated administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in C_max by approximately 25-30% and a delay in T_max to approximately 2.5 hours. However, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin bioavailability.

Distribution.

In preclinical studies, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the apparent volume of distribution of pregabalin following oral administration is approximately 0.56 L/kg. Pregabalin is not bound to plasma proteins. At clinical doses of 150 to 600 mg/day, the average steady-state plasma pregabalin concentrations were approximately 1.5 and 6.0 microgram/mL, respectively.

Metabolism.

Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin, approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, there was no indication of racemisation of pregabalin S-enantiomer to the R-enantiomer.

Excretion.

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Renal clearance (CL_cr) derived from Phase I studies was 73 mL/min.
Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance (see Special populations, Renal impairment).
Pregabalin clearance is reduced in patients with impaired renal function (see Section 4.2 Dose and Method of Administration, Renal impairment, Table 1).

Linearity/ non-linearity.

Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (< 20%). Multiple dose pharmacokinetics are predictable from single-dose data.

Special populations.

Race.

Population pharmacokinetic analyses of the Phase 2/3 studies in patients with chronic pain, general anxiety disorder (GAD) or partial seizures showed that the relationship between daily dose and pregabalin exposure is similar among Caucasians, Blacks and Hispanics.

Gender.

Population pharmacokinetic analyses of the Phase 2/3 studies in patients with chronic pain, GAD or partial seizures showed that the relationship between daily dose and pregabalin drug exposure is similar between genders when adjusted for gender-related differences in CL_cr.