PREGABALIN - pregabalin capsule

United States - English - NLM (National Library of Medicine)

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Active ingredient:
PREGABALIN (UNII: 55JG375S6M) (PREGABALIN - UNII:55JG375S6M)
Available from:
A-S Medication Solutions
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Pregabalin capsule is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy • Management of postherpetic neuralgia • Adjunctive therapy for the treatment of partial-onset seizures in patients 17 years of age and older • Management of fibromyalgia • Management of neuropathic pain associated with spinal cord injury Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution products.  However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.     Pregabalin is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy [see Warnings and Precautions (5.2)]. Pregnancy Exposure Registry   There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pregabalin during pregnancy. To provide information rega
Product summary:
Product: 50090-4465 NDC: 50090-4465-0 90 CAPSULE in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
50090-4465-0

PREGABALIN - pregabalin capsule

A-S Medication Solutions

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Medication Guide

Pregabalin (pree-GAH-ba-lin)

Capsules, CV

Read this Medication Guide before you start taking pregabalin and each time you get a refill. There may be

new information. This information does not take the place of talking to your healthcare provider about your

medical condition or treatment. If you have any questions about pregabalin, ask your healthcare provider or

pharmacist.

What is the most important information I should know about pregabalin?

Pregabalin may cause serious side effects including:

serious, even life-threatening, allergic

reactions

swelling of your hands, legs and

feet

suicidal thoughts or actions

dizziness and sleepiness

These serious side effects are described below:

· Serious, even life-threatening, allergic reactions.

Stop taking pregabalin and call your healthcare provider right away if you have any of these signs of a

serious allergic reaction:

o swelling of your face, mouth, lips, gums, tongue, throat or neck

o trouble breathing

o rash, hives (raised bumps) or blisters

· Like other antiepileptic drugs, pregabalin may cause suicidal thoughts or actions in a very small

number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms,

especially if they are new, worse, or worry you:

o thoughts about suicide or

dying

o trouble sleeping (insomnia)

o attempts to commit suicide

o new or worse irritability

o new or worse depression

o acting aggressive, being angry, or violent

o new or worse anxiety

o acting on dangerous impulses

o feeling agitated or restless

o an extreme increase in activity and talking

(mania)

o panic attacks

o other unusual changes in behavior or mood

If you have suicidal thoughts or actions, do not stop pregabalin without first talking to a healthcare provider.

Stopping pregabalin suddenly can cause serious problems.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal

thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

· Swelling of your hands, legs and feet. This swelling can be a serious problem for people with heart

problems.

· Dizziness and sleepiness. Do not drive a car, work with machines, or do other dangerous activities

until you know how pregabalin affects you. Ask your healthcare provider about when it will be okay to do

these activities.

What is pregabalin?

Pregabalin is a prescription medicine used in adults, 18 years of age and older to treat:

pain from damaged nerves (neuropathic pain) that happens with diabetes

pain from damaged nerves (neuropathic pain) that follows healing of shingles

fibromyalgia (pain all over your body)

pain from damaged nerves (neuropathic pain) that follows spinal cord injury

It is not known if pregabalin is safe and effective in people under 18 years of age for the treatment of

fibromyalgia and neuropathic pain with diabetes, shingles, or spinal cord injury.

Pregabalin is a prescription medicine used in people 17 years of age and older to treat:

partial-onset seizures when taken together with other seizure medicines.

For the treatment of partial-onset seizures when taken together with other seizure medicines, it is not known

if pregabalin is safe and effective in children under 1 month of age.

Who should not take pregabalin?

Do not take pregabalin capsules if you are allergic to pregabalin or any of the ingredients in pregabalin

capsules.

See “What is the most important information I should know about pregabalin?” for the signs of an allergic

reaction.

See the end of this Medication Guide for a complete list of ingredients in pregabalin.

What should I tell my healthcare provider before taking pregabalin?

Before taking pregabalin, tell your healthcare provider about all your medical conditions, including if you:

· have or have had depression, mood problems or suicidal thoughts or behavior.

· have kidney problems or get kidney dialysis.

· have heart problems including heart failure.

· have a bleeding problem or a low blood platelet count.

· have abused prescription medicines, street drugs, or alcohol in the past.

· have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema).

· plan to father a child. Animal studies have shown that pregabalin, the active ingredient in pregabalin,

made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen

in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can

happen in people who take pregabalin.

· are pregnant or plan to become pregnant. Pregabalin may harm your unborn baby. You and your

healthcare provider will decide if you should take pregabalin while you are pregnant.

o If you become pregnant while taking pregabalin, talk to your healthcare provider about registering with

the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-

233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during

pregnancy. Information about the registry can also be found at the web site,

http://www.aedpregnancyregistry.org/.

· are breastfeeding or plan to breastfeed. Pregabalin passes into your breast milk. It is not known if

pregabalin can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you

take pregabalin. Breastfeeding is not recommended while taking pregabalin.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter

medicines, vitamins or herbal supplements. Pregabalin and other medicines may affect each other causing

side effects. Especially tell your healthcare provider if you take:

· angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including

high blood pressure. You may have a higher chance for swelling and hives if these medicines are taken with

pregabalin.

Avandia (rosiglitazone) or Actos (pioglitazone) for diabetes. You may have a higher chance of weight gain

or swelling of your hands or feet if these medicines are taken with pregabalin.

· any narcotic pain medicine (such as oxycodone), tranquilizers or medicines for anxiety (such as

lorazepam). You may have a higher chance for dizziness and sleepiness if these medicines are taken with

pregabalin.

· any medicines that make you sleepy.

Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist

each time you get a new medicine. Do not start a new medicine without talking with your healthcare

provider.

How should I take pregabalin?

· Take pregabalin exactly as prescribed. Your healthcare provider will tell you how much pregabalin to

take and when to take it.

· Pregabalin may be taken with or without food.

· Your healthcare provider may change your dose. Do not change your dose without talking to your

healthcare provider.

· Do not stop taking pregabalin without talking to your healthcare provider. If you stop taking

pregabalin suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you

may feel anxious. If you have epilepsy and you stop taking pregabalin suddenly, you may have seizures more

often. Talk with your healthcare provider about how to stop pregabalin slowly.

· If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, just skip the

missed dose. Take the next dose at your regular time. Do not take two doses at the same time.

· If you take too much pregabalin, call your healthcare provider or poison control center, or go to the

nearest emergency room right away.

What should I avoid while taking pregabalin?

· Do not drive a car, work with machines, or do other dangerous activities until you know how

pregabalin affects you.

· Do not drink alcohol while taking pregabalin. Pregabalin and alcohol can affect each other and

increase side effects such as sleepiness and dizziness.

What are the possible side effects of pregabalin?

Pregabalin may cause serious side effects, including:

· See “What is the most important information I should know about pregabalin?"

· Muscle problems, muscle pain, soreness, or weakness. If you have these symptoms, especially if you

feel sick and have a fever, tell your healthcare provider right away.

· Problems with your eyesight, including blurry vision. Call your healthcare provider if you have any

changes in your eyesight.

· Weight gain. If you have diabetes, weight gain may affect the management of your diabetes. Weight

gain can also be a serious problem for people with heart problems.

· Feeling "high".

The most common side effects of pregabalin are:

dizziness

weight gain trouble concentrating

blurry

vision

sleepiness

swelling of hands and

feet

dry mouth

Pregabalin caused skin sores in animal studies. Skin sores did not happen in studies in people. If you have

diabetes, you should pay attention to your skin while taking pregabalin and tell your healthcare provider

about any sores or skin problems.

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of pregabalin. For more information, ask your healthcare provider

or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-

1088.

How should I store pregabalin?

· Store pregabalin capsul e at 25 °C (77°F); e xcursions pe r mitted to 15°C to 30°C (59°F to 86°F) (see

USP Controlled Room T e m perature) in its o riginal package.

· Safely throw away any pregabalin that is out of date or no longer needed.

Keep pregabalin and all medicines out of the reach of children.

General information about the safe and effective use of pregabalin

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use

pregabalin for a condition for which it was not prescribed. Do not give pregabalin to other people, even if

they have the same symptoms you have. It may harm them. You can ask your healthcare provider or

pharmacist for information about pregabalin that is written for health professionals.

For more information call Alembic Pharmaceuticals Limited at 1-866-210-9797.

What are the ingredients in pregabalin?

Active i ng re die nt: pre ga balin

Inactive ingredients: corn starch and talc

The caps ule shells contain gelatin and titanium dioxide. In addition, the orange capsule shells contain red

iron oxide which is used in 50 mg, 75 mg, 100 mg, 200 mg, 225 mg and 300 mg strength of pregabalin

capsules. The i mprinting ink contains shellac, propylene glycol, black iron oxide, and potassium hydroxide.

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution

products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that

pediatric information.

This Medication Guide has been approved by t he U.S. Food and Drug A dm in istration.

Trademarks are the property of their respective owners.

Medication Guide available at http://www.alembicusa.com/medicationguide.aspx or call 1-866-210-9797.

Manufactured by:

Alembic Pharmaceuticals Limited

(Formulation Division),

Panelav 389350, Gujarat, India

Manufactured for:

Alembic Pharmaceuticals, Inc.

750 Route 202, Bridgewater, NJ 08807

Revised: 07/2019

Revised: 8/2019

Document Id: f900fe69-1b6f-4bc6-9f62-978eab36a41e

34391-3

Set id: 3332ed8a-90b8-45d0-87bd-e8fc4262cb58

Version: 1

Effective Time: 20190828

A-S Medication Solutions

PREGABALIN - pregabalin capsule

A-S Medication Solutions

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PREGABALIN CAPSULES safely and

effectively. See full prescribing information for PREGABALIN CAPSULES.

PREGABALIN capsules for oral use CV

Initial U.S. Approval: 2004

INDICATIONS AND USAGE

Pregabalin capsule is indicated for:

Neuropathic pain associated with diabetic peripheral neuropathy (DPN) (1)

Postherpetic neuralgia (PHN) (1)

Adjunctive therapy for the treatment of partial-onset seizures in patients 17 years of age and older (1)

Fibromyalgia (1)

Neuropathic pain associated with spinal cord injury (1) (1)

DOSAGE AND ADMINISTRATION

For adult indications, begin dosing at 150 mg/day. (2.2, 2.3, 2.4, 2.5, 2.6)

Dosing recommendations: (2)

INDICATION

Dosing Regimen Maximum Dose

DPN Pain (2.2)

3 divided doses

per day

300 mg/day within 1 week

PHN (2.3)

2 or 3 divided

doses per day

300 mg/day within 1 week. Maximum

dose of 600 mg/day.

Adjunctive Therapy for Partial-Onset Seizures in Patients 17

Years of Age and Older (2.4)

2 or 3 divided

doses per day

Maximum dose of 600 mg/day.

Fibromyalgia (2.5)

2 divided doses

per day

300 mg/day within 1 week. Maximum

dose of 450 mg/day.

Neuropathic Pain Associated with Spinal Cord Injury (2.6)

2 divided doses

per day

300 mg/day within 1 week. Maximum

dose of 600 mg/day.

Dose should be adjusted in adult patients with reduced renal function. (2.7) (2)

DOSAGE FORMS AND STRENGTHS

Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg. (3) (3)

CONTRAINDICATIONS

Known hypersensitivity to pregabalin or any of its components. (4)

WARNINGS AND PRECAUTIONS

Angioedema (e.g., swelling of the throat, head and neck) can occur, and may be associated with life-threatening

respiratory compromise requiring emergency treatment. Discontinue pregabalin immediately in these cases. (5.1)

Hypersensitivity reactions (e.g. hives, dyspnea, and wheezing) can occur. Discontinue pregabalin immediately in these

patients. (5.2)

Increased seizure frequency or other adverse reactions may occur if pregabalin is rapidly discontinued. Withdraw

pregabalin gradually over a minimum of 1 week. (5.3)

Antiepileptic drugs, including pregabalin, increase the risk of suicidal thoughts or behavior. (5.4)

Pregabalin may cause peripheral edema. Exercise caution when co-administering pregabalin and thiazolidinedione

antidiabetic agents. (5.5)

Pregabalin may cause dizziness and somnolence and impair patients’ ability to drive or operate machinery.(5.6) (5)

ADVERSE REACTIONS

Most common adverse reactions (greater than or equal to 5% and twice placebo) in adults are dizziness, somnolence, dry

mouth, edema, blurred vision, weight gain, and thinking abnormal (primarily difficulty with concentration/attention). (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797

or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Pregnancy: May cause fetal harm. Advise of potential risk to the fetus.(8.1 )

Lactation: Breastfeeding is not recommended. (8.2)

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution products. However, due

to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. (8)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

2.2 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy in Adults

2.3 Postherpetic Neuralgia in Adults

2.4 Adjunctive Therapy for Partial-Onset Seizures in Patients 17 Years of Age and Older

2.5 Management of Fibromyalgia in Adults

2.6 Neuropathic Pain Associated with Spinal Cord Injury in Adults

2.7 Dosing for Adult Patients with Renal Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Angioedema

5.2 Hypersensitivity

5.3 Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation

5.4 Suicidal Behavior and Ideation

5.5 Peripheral Edema

5.6 Dizziness and Somnolence

5.7 Weight Gain

5.8 Tumorigenic Potential

5.9 Ophthalmological Effects

5.10 Creatine Kinase Elevations

5.11 Decreased Platelet Count

5.12 PR Interval Prolongation

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis,Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

14.2 Postherpetic Neuralgia

14.3 Adjunctive Therapy for Partial-Onset Seizures in Patients 17 Years of Age and Older

14.4 Management of Fibromyalgia

14.5 Management of Neuropathic Pain Associated with Spinal Cord Injury

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

Pregabalin capsule is indicated for:

Management of neuropathic pain associated with diabetic peripheral neuropathy

Management of postherpetic neuralgia

Adjunctive therapy for the treatment of partial-onset seizures in patients 17 years of age and

older

Management of fibromyalgia

Management of neuropathic pain associated with spinal cord injury

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution

products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that

pediatric information.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

Pregabalin is given orally with or without food.

When discontinuing pregabalin, taper gradually over a minimum of 1 week [see Warnings and

Precautions (5.3)].

Because pregabalin is eliminated primarily by renal excretion, adjust the dose in adult patients with

reduced renal function [see Dosage and Administration (2.7)].

2.2 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy in Adults

The maximum recommended dose of pregabalin is 100 mg three times a day (300 mg/day) in patients

with creatinine clearance of at least 60 mL/min. Begin dosing at 50 mg three times a day (150 mg/day).

The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

Although pregabalin was also studied at 600 mg/day, there is no evidence that this dose confers

additional significant benefit and this dose was less well tolerated. In view of the dose-dependent

adverse reactions, treatment with doses above 300 mg/day is not recommended [see Adverse Reactions

(6.1)].

2.3 Postherpetic Neuralgia in Adults

The recommended dose of pregabalin is 75 to 150 mg two times a day, or 50 to 100 mg three times a

day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 75

mg two times a day, or 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day

within 1 week based on efficacy and tolerability.

Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 300

mg/day, and who are able to tolerate pregabalin, may be treated with up to 300 mg two times a day, or

200 mg three times a day (600 mg/day). In view of the dose-dependent adverse reactions and the higher

rate of treatment discontinuation due to adverse reactions, reserve dosing above 300 mg/day for those

patients who have on-going pain and are tolerating 300 mg daily [see Adverse Reactions (6.1)].

2.4 Adjunctive Therapy for Partial-Onset Seizures in Patients 17 Years of Age and Older

The recommended dosage for adult patients 17 years of age and older is included in Table 1.

Administer the total daily dosage orally in two or three divided doses as indicated in Table1. Based on

clinical response and tolerability, dosage may be increased, approximately weekly.

Table 1. Recommended Dosage for Adult Patients 17 Years and Older

Age and BodyRecommended InitialRecommended

Frequency

of

Weight

Dosage

Maximum Dosage

Administration

Adults

years and older)

150 mg/day

600 mg/day

2 or 3 divided doses

Both the efficacy and adverse event profiles of pregabalin have been shown to be dose-related.

The effect of dose escalation rate on the tolerability of pregabalin has not been formally studied.

The efficacy of adjunctive pregabalin in patients taking gabapentin has not been evaluated in controlled

trials. Consequently, dosing recommendations for the use of pregabalin with gabapentin cannot be

offered.

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution

products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that

pediatric information.

2.5 Management of Fibromyalgia in Adults

The recommended dose of pregabalin for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg

two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day)

within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with

300 mg/day may be further increased to 225 mg two times a day (450 mg/day). Although pregabalin was

also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose

was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above

450 mg/day is not recommended [see Adverse Reactions (6.1)].

2.6 Neuropathic Pain Associated with Spinal Cord Injury in Adults

The recommended dose range of pregabalin for the treatment of neuropathic pain associated with spinal

cord injury is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150

mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on

efficacy and tolerability. Patients who do not experience sufficient pain relief after 2 to 3 weeks of

treatment with 150 mg two times a day and who tolerate pregabalin may be treated with up to 300 mg two

times a day [see Clinical Studies (14.5)].

2.7 Dosing for Adult Patients with Renal Impairment

In view of dose-dependent adverse reactions and since pregabalin is eliminated primarily by renal

excretion, adjust the dose in adult patients with reduced renal function. The use of pregabalin in

pediatric patients with compromised renal function has not been studied.

Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in

Table 2. To use this dosing table, an estimate of the patient's CLcr in mL/min is needed. CLcr in mL/min

may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:

Next, refer to the Dosage and Administration section to determine the recommended total daily dose

based on indication, for a patient with normal renal function (CLcr greater than or equal to 60 mL/min).

Then refer to Table 2 to determine the corresponding renal adjusted dose.

(For example: A patient initiating pregabalin therapy for postherpetic neuralgia with normal renal

function (CLcr greater than or equal to 60 mL/min), receives a total daily dose of 150 mg/day

pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily

dose of 75 mg/day pregabalin administered in two or three divided doses.)

For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In

addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-

hour hemodialysis treatment (see Table 2).

Table 2. Pregabalin Dosage Adjustment Based on Renal Function

Creatinine Clearance (CLcr)

(mL/min)

Total Pregabalin Daily Dose (mg/day)*

Dose Regimen

Greater than or equal to 60

BID or TID

30 to 60

BID or TID

15 to 30

25 to 50

100 to 150

QD or BID

Less than 15

25 to 50

50 to 75

Supplementary dosage following hemodialysis (mg)

Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg

Patients on the 25 to 50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg

Patients on the 50 to 75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg

Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg

TID= Three divided doses; BID = Two divided doses;QD = Single daily dose.

*Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.

Supplementary dose is a single additional dose.

3 DOSAGE FORMS AND STRENGTHS

Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg

[see Description (11) and How Supplied/Storage and Handling (16)]

4 CONTRAINDICATIONS

Pregabalin is contraindicated in patients with known hypersensitivity to pregabalin or any of its

components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin

therapy [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Angioedema

There have been postmarketing reports of angioedema in patients during initial and chronic treatment

with pregabalin. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and

neck (throat and larynx). There were reports of life-threatening angioedema with respiratory

compromise requiring emergency treatment. Discontinue pregabalin immediately in patients with these

symptoms.

Exercise caution when prescribing pregabalin to patients who have had a previous episode of

angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g.,

angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing

angioedema.

5.2 Hypersensitivity

There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment

There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment

with pregabalin. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing.

Discontinue pregabalin immediately in patients with these symptoms.

5.3 Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation

As with all antiepileptic drugs (AEDs), withdraw pregabalin gradually to minimize the potential of

increased seizure frequency in patients with seizure disorders.

Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including

insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea.

If pregabalin is discontinued, taper the drug gradually over a minimum of 1 week rather than discontinue

the drug abruptly.

5.4 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including pregabalin, increase the risk of suicidal thoughts or behavior in

patients taking these drugs for any indication. Monitor patients treated with any AED for any indication

for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual

changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different

AEDs showed that patients randomized 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 behavior compared to patients randomized to

placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate

of suicidal behavior 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 behavior 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 behavior 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

behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

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 to 100 years) in the clinical trials analyzed.

Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication

Placebo Patients with

Events Per 1000

Patients

Drug Patients with

Events Per 1000

Patients

Relative Risk: Incidence of

Events in Drug

Patients/Incidence in Placebo

Patients

Risk Difference:

Additional Drug

Patients withEvents

Per 1000 Patients

Epilepsy

Psychiatric

Other

Total

The relative risk for suicidal thoughts or behavior 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 the risk of suicidal thoughts

or behavior 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 behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber

needs to consider whether the emergence of these symptoms in any given patient may berelated to the

illness being treated.

5.5 Peripheral Edema

Pregabalin treatment may cause peripheral edema. In short-term trials of patients without clinically

significant heart or peripheral vascular disease, there was no apparent association between peripheral

edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral

edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic

function.

In controlled clinical trials in adult patients, the incidence of peripheral edema was 6% in the

pregabalin group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of

pregabalin patients and 0.2% placebo patients withdrew due to peripheral edema.

Higher frequencies of weight gain and peripheral edema were observed in patients taking both

pregabalin and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The

majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were

participants in studies of pain associated with diabetic peripheral neuropathy. In this population,

peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic

agents only, 8% (69/859) of patients who were treated with pregabalin only, and 19% (23/120) of

patients who were on both pregabalin and thiazolidinedione antidiabetic agents. Similarly, weight gain

was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on pregabalin

only; and 7.5% (9/120) of patients on both drugs.

As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention,

possibly exacerbating or leading to heart failure, exercise caution when co-administering pregabalin

and these agents.

Because there are limited data on congestive heart failure patients with New York Heart Association

(NYHA) Class III or IV cardiac status, exercise caution when using pregabalin in these patients.

5.6 Dizziness and Somnolence

Pregabalin may cause dizziness and somnolence. Inform patients that pregabalin-related dizziness and

somnolence may impair their ability to perform tasks such as driving or operating machinery [see Patient

Counseling Information (17)].

In the pregabalin controlled trials in adult patients, dizziness was experienced by 30% of pregabalin-

treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of

pregabalin-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence

generally began shortly after the initiation of pregabalin therapy and occurred more frequently at higher

doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4%

each) from controlled studies. In pregabalin-treated patients reporting these adverse reactions in short-

term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until

the last dose in 42% of patients [see Drug Interactions (7)].

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution

products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that

pediatric information.

5.7 Weight Gain

Pregabalin treatment may cause weight gain. In pregabalin controlled clinical trials in adult patients of

up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of pregabalin-treated

patients and 2% of placebo-treated patients. Few patients treated with pregabalin (0.3%) withdrew from

controlled trials due to weight gain. Pregabalin associated weight gain was related to dose and duration

of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not

limited to patients with edema [see Warnings and Precautions (5.5)].

Although weight gain was not associated with clinically important changes in blood pressure in short-

term controlled studies, the long-term cardiovascular effects of pregabalin-associated weight gain are

unknown.

Among diabetic patients, pregabalin-treated patients gained an average of 1.6 kg (range: -16 to 16 kg),

compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333

diabetic patients who received pregabalin for at least 2 years, the average weight gain was 5.2 kg.

While the effects of pregabalin-associated weight gain on glycemic control have not been

systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients,

pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by

5.8 Tumorigenic Potential

In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, an unexpectedly high

incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical

Toxicology (13.1)]. The clinical significance of this finding is unknown. Clinical experience during

pregabalin’s premarketing development provides no direct means to assess its potential for inducing

tumors in humans.

In clinical studies across various patient populations, comprising 6396 patient-years of exposure in

patients greater than 12 years of age, new or worsening-preexisting tumors were reported in 57 patients.

Without knowledge of the background incidence and recurrence in similar populations not treated with

pregabalin, it is impossible to know whether the incidence seen in these cohorts is or is not affected by

treatment.

5.9 Ophthalmological Effects

In controlled studies in adult patients, a higher proportion of patients treated with pregabalin reported

blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases

with continued dosing. Less than 1% of patients discontinued pregabalin treatment due to vision-related

events (primarily blurred vision).

Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing

and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual

acuity was reduced in 7% of patients treated with pregabalin, and 5% of placebo-treated patients. Visual

field changes were detected in 13% of pregabalin-treated, and 12% of placebo-treated patients.

Funduscopic changes were observed in 2% of pregabalin-treated and 2% of placebo-treated patients.

Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify

their physician if changes in vision occur. If visual disturbance persists, consider further assessment.

Consider more frequent assessment for patients who are already routinely monitored for ocular

conditions [see Patient Counseling Information (17)].

5.10 Creatine Kinase Elevations

Pregabalin treatment 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 in adult patients across multiple patient populations, 1.5% of

patients on pregabalin and 0.7% 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. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness,

particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with

pregabalin if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.

5.11 Decreased Platelet Count

Pregabalin treatment was associated with a decrease in platelet count. Pregabalin-treated subjects

experienced a mean maximal decrease in platelet count of 20 × 10 /μL, compared to 11 × 10 /μL in

placebo patients. In the overall database of controlled trials in adult patients, 2% of placebo patients and

3% of pregabalin patients experienced a potentially clinically significant decrease in platelets, defined

as 20% below baseline value and less than 150 × 10 /μL. A single pregabalin treated subject developed

severe thrombocytopenia with a platelet count less than 20 x 10 / μL. In randomized controlled trials,

pregabalin was not associated with an increase in bleeding-related adverse reactions.

5.12 PR Interval Prolongation

Pregabalin treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data

in adult patients, the mean PR interval increase was 3 to 6 msec at pregabalin doses greater than or equal

to 300 mg/day. This mean change difference was not associated with an increased risk of PR increase

greater than or equal to 25% from baseline, an increased percentage of subjects with on-treatment PR

greater than 200 msec, or an increased risk of adverse reactions of second or third degree AV block.

Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR

prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be

considered definitive because of the limited number of patients in these categories.

6 ADVERSE REACTIONS

Angioedema [see Warnings and Precautions (5.1)]

Hypersensitivity [see Warnings and Precautions (5.2)]

Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation [see Warnings and

Precautions (5.3)]

Suicidal Behavior and Ideation [see Warnings and Precautions (5.4)]

Peripheral Edema [see Warnings and Precautions (5.5)]

Dizziness and Somnolence [see Warnings and Precautions (5.6)]

Weight Gain [see Warnings and Precautions (5.7)]

Tumorigenic Potential [see Warnings and Precautions (5.8)]

Ophthalmological Effects [see Warnings and Precautions (5.9)]

Creatine Kinase Elevations [see Warnings and Precautions (5.10)]

Decreased Platelet Count [see Warnings and Precautions (5.11)]

PR Interval Prolongation [see Warnings and Precautions (5.12)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

In all controlled and uncontrolled trials across various patient populations during the premarketing

development of pregabalin, more than 10,000 patients have received pregabalin. Approximately 5000

patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and

over 1400 patients were treated for at least 2 years.

Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical

Studies

In premarketing controlled trials of all adult populations combined, 14% of patients treated with

pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In

the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were

dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness

and less than 1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from

controlled trials more frequently in the pregabalin group compared to the placebo group were ataxia,

confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).

Most Common Adverse Reactions in All Controlled Clinical Studies in Adults

In premarketing controlled trials of all adult patient populations combined (including DPN, PHN, and

adult patients with partial-onset seizures), dizziness, somnolence, dry mouth, edema, blurred vision,

weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more

commonly reported by subjects treated with pregabalin than by subjects treated with placebo (greater

than or equal to 5% and twice the rate of that seen in placebo).

Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

Adverse Reactions Leading to Discontinuation

In clinical trials in adults with neuropathic pain associated with diabetic peripheral neuropathy, 9% of

patients treated with pregabalin and 4% of patients treated with placebo discontinued prematurely due to

adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due

to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, less than 1% of placebo

patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials,

occurring with greater frequency in the pregabalin group than in the placebo group, were asthenia,

confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of

patients.

Most Common Adverse Reactions

Table 4 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of

patients with neuropathic pain associated with diabetic neuropathy in the combined pregabalin group for

which the incidence was greater in this combined pregabalin group than in the placebo group. A

majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity

of “mild” or “moderate”.

Table 4. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with

Diabetic Peripheral Neuropathy

Body system

Preferred term

75 mg/day

[N=77] %

150 mg/day

[N=212] %

300 mg/day

[N=321] %

600 mg/day

[N=369] %

All PGB

[N=979] %

Placebo

[N=459] %

Body as a whole

Asthenia

Accidental injury

Back pain

Chest pain

Face edema

Digestive system

Dry mouth

Constipation

Flatulence

Metabolic and nutritional

disorders

Peripheral edema

Weight gain

Edema

Hypoglycemia

Nervous system

Dizziness

Somnolence

Neuropathy

Ataxia

Vertigo

Confusion

Euphoria

Incoordination

Thinking abnormal

Tremor

Abnormal gait

Amnesia

Nervousness

Respiratory system

Dyspnea

*

Special senses

Blurry vision

Abnormal vision

* PGB: pregabalin

Thinking abnormal primarily consists of events related to difficulty with concentration/attention but

also includes events related to cognition and language problems and slowed thinking.

Investigator term; summary level term is amblyopia

Controlled Studies in Postherpetic Neuralgia

Adverse Reactions Leading to Discontinuation

In clinical trials in adults with postherpetic neuralgia, 14% of patients treated with pregabalin and 7% of

patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin

treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness

(4%) and somnolence (3%). In comparison, less than 1% of placebo patients withdrew due to dizziness

and somnolence. Other reasons for discontinuation from the trials, occurring in greater frequency in the

pregabalin group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia,

ataxia, and abnormal gait (1% each).

Most Common Adverse Reactions

Table 5 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of

patients with neuropathic pain associated with postherpetic neuralgia in the combined pregabalin group

for which the incidence was greater in this combined pregabalin group than in the placebo group. In

addition, an event is included, even if the incidence in the all pregabalin group is not greater than in the

placebo group, if the incidence of the event in the 600 mg/day group is more than twice that in the

placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a

maximum intensity of “mild” or “moderate”. Overall, 12.4% of all pregabalin-treated patients and 9% of

all placebo-treated patients had at least one severe event while 8% of pregabalin-treated patients and

4.3% of placebo-treated patients had at least one severe treatment-related adverse event.

Table 5. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with

Postherpetic Neuralgia

Body system Preferred

term

75 mg/d

[N=84] %

150 mg/d

[N=302] %

300 mg/d

[N=312] %

600 mg/d

[N=154] %

All PGB

[N=852] %

Placebo

[N=398] %

Body as a whole

Infection

Headache

Pain

Accidental injury

Flu syndrome

Face edema

Digestive system

Dry mouth

Constipation

Flatulence

Vomiting

Metabolic and nutritional disorders

Peripheral edema

Weight gain

Edema

Musculoskeletal system

Myasthenia

Nervous system

Dizziness

Somnolence

Ataxia

Abnormal gait

Confusion

Thinking abnormal

Incoordination

*

Amnesia

Speech disorder

Respiratory system

Bronchitis

Special senses

Blurry vision

Diplopia

Abnormal vision

Eye Disorder

Urogenital System

Urinary Incontinence

* PGB: pregabalin

Thinking abnormal primarily consists of events related to difficulty with concentration/attention but

also includes events related to cognition and language problems and slowed thinking.

Investigator term; summary level term is amblyopia

Controlled Studies of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients

Adverse Reactions Leading to Discontinuation

Approximately 15% of patients receiving pregabalin and 6% of patients receiving placebo in trials of

adjunctive therapy for partial-onset seizures discontinued prematurely due to adverse reactions. In the

pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were

dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, less than 1% of patients in the

placebo group withdrew due to each of these events. Other adverse reactions that led to discontinuation

of at least 1% of patients in the pregabalin group and at least twice as frequently compared to the

placebo group were asthenia, diplopia, blurred vision, thinking abnormal, nausea, tremor, vertigo,

headache, and confusion (which each led to withdrawal in 2% or less of patients).

Most Common Adverse Reactions

Table 6 lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-treated

patients. Dose-relatedness was defined as the incidence of the adverse event in the 600 mg/day group

was at least 2% greater than the rate in both the placebo and 150 mg/day groups. In these studies, 758

patients received pregabalin and 294 patients received placebo for up to 12 weeks. A majority of

pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild"

or "moderate".

Table 6. Dose-related Adverse Reaction Incidence in Controlled Trials of Adjunctive Therapy

for Partial-Onset Seizures in Adult Patients

Body System

Preferred Term

150 mg/d

[N = 185]

%

300 mg/d

[N = 90] %

600 mg/d

[N = 395]

%

All PGB*

[N = 670]†

%

Placebo

[N = 294] %

Body as a Whole

Accidental Injury

Pain

Digestive System

Increased Appetite

Dry Mouth

Constipation

Metabolic and Nutritional

Dis orders

Weight Gain

Peripheral Edema

Nervous System

Dizziness

Somnolence

Ataxia

Tremor

Thinking Abnormal

Amnesia

Speech Disorder

Incoordination

Abnormal Gait

Twitching

Confusion

Myoclonus

Special Senses

Blurred Vision

Diplopia

Abnormal Vision

PGB: pregabalin

Excludes patients who received the 50 mg dose in Study E1.

Thinking abnormal primarily consists of events related to difficulty with concentration/attention but

also includes events related to cognition and language problems and slowed thinking.

Investigator term; summary level term is amblyopia.

Controlled Studies with Fibromyalgia

Adverse Reactions Leading to Discontinuation

In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150 to 600

mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In

the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions

were dizziness (6%) and somnolence (3%). In comparison, less than 1% of placebo-treated patients

withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring

with greater frequency in the pregabalin treatment group than in the placebo treatment group, were

fatigue, headache, balance disorder, and weight increased. Each of these adverse reactions led to

withdrawal in approximately 1% of patients.

Most Common Adverse Reactions

Table 9 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of

patients with fibromyalgia in the ‘all pregabalin’ treatment group for which the incidence was greater

than in the placebo treatment group. A majority of pregabalin-treated patients in clinical studies

experienced adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 9. Adverse Reaction Incidence in Controlled Trials in Fibromyalgia

System Organ Class

Preferred term

150 mg/d

[N=132]

%

300 mg/d

[N=502]

%

450 mg/d

[N=505]

%

600 mg/d

[N=378]

%

All PGB

[N=1517]

%

Placebo

[N=505]

%

Ear and Labyrinth Disorders

Vertigo

Eye Disorders

Vision blurred

Gastrointestinal Disorders

Dry mouth

Constipation

Vomiting

Flatulence

Abdominal distension

General Disorders and Administrative Site Conditions

Fatigue

Edema peripheral

Chest pain

Feeling abnormal

Edema

Feeling drunk

Infections and Infestations

Sinusitis

Investigations

Weight increased

Metabolism and Nutrition Disorders

*

Metabolism and Nutrition Disorders

Increased appetite

Fluid retention

Musculoskeletal and Connective Tissue Disorders

Arthralgia

Muscle spasms

Back pain

Nervous System Disorders

Dizziness

Somnolence

Headache

Disturbance in

attention

Balance disorder

Memory impairment

Coordination abnormal

Hypoesthesia

Lethargy

Tremor

Psychiatric Disorders

Euphoric Mood

Confusional state

Anxiety

Disorientation

Depression

Respiratory, Thoracic and Mediastinal Disorders

Pharyngolaryngeal

pain

* PGB: Pregabalin

Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury

Adverse Reactions Leading to Discontinuation

In clinical trials of adults with neuropathic pain associated with spinal cord injury, 13% of patients

treated with pregabalin and 10% of patients treated with placebo discontinued prematurely due to

adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due

to adverse reactions were somnolence (3%) and edema (2%). In comparison, none of the placebo-treated

patients withdrew due to somnolence and edema. Other reasons for discontinuation from the trials,

occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group,

were fatigue and balance disorder. Each of these adverse reactions led to withdrawal in less than 2% of

patients.

Most Common Adverse Reactions

Table 10 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of

patients for which the incidence was greater than in the placebo treatment group with neuropathic pain

associated with spinal cord injury in the controlled trials. A majority of pregabalin-treated patients in

clinical studies experienced adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 10. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with

Spinal Cord Injury

System Organ Class

Preferred term

PGB* (N=182)

%

Placebo (N=174)

%

Ear and labyrinth disorders

Vertigo

Eye disorders

Vision blurred

Gastrointestinal disorders

Dry mouth

Constipation

Nausea

Vomiting

General disorders and administration site conditions

Fatigue

Edema peripheral

10.4

Edema

Pain

Infections and infestations

Nasopharyngitis

Investigations

Weight increased

Blood creatine phosphokinase increased

Musculoskeletal and connective tissue disorders

Muscular weakness

Pain in extremity

Neck pain

Back pain

Joint swelling

Nervous system disorders

Somnolence

35.7

11.5

Dizziness

20.9

Disturbance in attention

Memory impairment

Paresthesia

Psychiatric disorders

Insomnia

Euphoric mood

Renal and urinary disorders

Urinary incontinence

Skin and subcutaneous tissue disorders

Decubitus ulcer

Vascular disorders

Hypertension

Hypotension

* PGB: Pregabalin

Other Adverse Reactions Observed During the Clinical Studies of Pregabalin

Following is a list of treatment-emergent adverse reactions reported by patients treated with pregabalin

during all clinical trials. The listing does not include those events already listed in the previous tables

or elsewhere in labeling, those events for which a drug cause was remote, those events which were so

general as to be uninformative, and those events reported only once which did not have a substantial

probability of being acutely life-threatening.

Events are categorized by body system and listed in order of decreasing frequency according to the

following definitions: frequent adverse reactions are those occurring on one or more occasions in at

least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare

reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are

described in the Warnings and Precautions section (5).

Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent: Abscess, Cellulitis,

Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Rare: Anaphylactoid

reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock

Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural

hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation

Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis,

Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth

ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal

Ulcer, Periodontal abscess

Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic

anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis,

Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia, Alanine aminotransferase increased,

Aspartate aminotransferase increased

Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria

Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent:

Arthrosis; Rare: Chondrodystrophy, Generalized Spasm

Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased,

Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy,

Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia,

Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction,

Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia,

Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial

hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic

depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus

Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung

fibrosis, Yawn

Skin and Appendages – Frequent: Pruritus, Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin

ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis,

Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin

nodule, Stevens-Johnson syndrome, Subcutaneous nodule

Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of

accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema,

Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular

palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic

atrophy, Papilledema, Parosmia, Ptosis, Uveitis

Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence;

Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria,

Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine

abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia,

Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis

Comparison of Gender and Race

The overall adverse event profile of pregabalin was similar between women and men. There are

insufficient data to support a statement regarding the distribution of adverse experience reports by race.

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution

products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that

pediatric information.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of pregabalin. Because

these reactions are reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders – Headache

Gastrointestinal Disorders – Nausea, Diarrhea

Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement

In addition, there are postmarketing 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. There are

also postmarketing reports of respiratory failure and coma in patients taking pregabalin and other CNS

depressant medications.

7 DRUG INTERACTIONS

Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in

humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins,

its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or

protein binding displacement. In vitro and in vivo studies showed that pregabalin is unlikely to be

involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic

interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid,

lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also

not be expected to occur between pregabalin and commonly used antiepileptic drugs [see Clinical

Pharmacology (12)].

Pharmacodynamics

Multiple oral doses of pregabalin were co-administered with oxycodone, lorazepam, or ethanol.

Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor

functioning were seen when pregabalin was co-administered with these drugs. No clinically important

effects on respiration were seen.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to

pregabalin during pregnancy. To provide information regarding the effects of in utero exposure to

pregabalin, physicians are advised to recommend that pregnant patients taking pregabalin enroll in the

North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll

free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can

also be found at the website http://www.aedpregnancyregistry.org/.

Risk Summary

There are no adequate and well-controlled studies with pregabalin in pregnant women. However, in

animal reproduction studies, increased incidences of fetal structural abnormalities and other

manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and

decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally

during organogenesis, at doses that produced plasma pregabalin exposures (AUC) greater than or equal

to 16 times human exposure at the maximum recommended dose (MRD) of 600 mg/day [see Data]. In an

animal development study, lethality, growth retardation, and nervous and reproductive system functional

impairment were observed in the offspring of rats given pregabalin during gestation and lactation. The

no-effect dose for developmental toxicity was approximately twice the human exposure at MRD. The

background risk of major birth defects and miscarriage for the indicated populations are unknown.

However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of

miscarriage is 15 to 20% of clinically recognized pregnancies. Advise pregnant women of the potential

risk to a fetus.

Data

Animal Data

When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of

organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification

(premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1250 mg/kg,

and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body

weights were decreased at the highest dose. The low dose in this study was associated with a plasma

exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose

for rat embryo-fetal developmental toxicity was not established.

When pregnant rabbits were given pregabalin (250, 500, or 1250 mg/kg) orally throughout the period of

organogenesis, decreased fetal body weight and increased incidences of skeletal malformations,

visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for

developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16

times human exposure at the MRD.

In a study in which female rats were dosed with pregabalin (50, 100, 250, 1250, or 2500 mg/kg)

throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg

and offspring survival was decreased at greater than or equal to 250 mg/kg. The effect on offspring

survival was pronounced at doses greater than or equal to 1250 mg/kg, with 100% mortality in high-

dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory

startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment

(decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre-and postnatal

developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human

exposure at the MRD.

In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures

greater than or equal to 50 times the mean human exposure (AUC

of 123 µg·hr/mL) at the MRD.

8.2 Lactation

Risk Summary

Small amounts of pregabalin have been detected in the milk of lactating women. A pharmacokinetic study

in lactating women detected pregabalin in breast milk at average steady state concentrations

approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin

from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a

mg/kg basis would be approximately 7% of the maternal dose [see Data]. The study did not evaluate the

effects of pregabalin on milk production or the effects of pregabalin on the breastfed infant.

Based on animal studies, there is a potential risk of tumorigenicity with pregabalin exposure via breast

milk to the breastfed infant [see Nonclinical Toxicology (13.1)]. Available clinical study data in patients

greater than 12 years of age do not provide a clear conclusion about the potential risk of tumorigenicity

with pregabalin [see Warnings and Precautions (5.8)]. Because of the potential risk of tumorigenicity,

breastfeeding is not recommended during treatment with pregabalin.

Data

A pharmacokinetic study in ten lactating women, who were at least 12 weeks postpartum, evaluated the

concentrations of pregabalin in plasma and breast milk. Pregabalin 150 mg oral capsule was given every

12 hours (300 mg daily dose) for a total of four doses. Pregabalin was detected in breast milk at

average steady-state concentrations approximately 76% of those in maternal plasma. The estimated

average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150

mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal

dose. The study did not evaluate the effects of pregabalin on milk production. Infants did not receive

breast milk obtained during the dosing period, therefore, the effects of pregabalin on the breast fed

infant were not evaluated.

8.3 Females and Males of Reproductive Potential

Infertility

Male

Effects on Spermatogenesis

In a randomized, double-blind, placebo-controlled non-inferiority study to assess the effect of

pregabalin on sperm characteristics, healthy male subjects received pregabalin at a daily dose up to 600

mg (n=111) or placebo (n=109) for 13 weeks (one complete sperm cycle) followed by a 13-week

washout period (off-drug). A total of 65 subjects in the pregabalin group (59%) and 62 subjects in the

placebo group (57%) were included in the per protocol (PP) population. These subjects took study drug

for at least 8 weeks, had appropriate timing of semen collections and did not have any significant

protocol violations. Among these subjects, approximately 9% of the pregabalin group (6/65) vs. 3% in

the placebo group (2/62) had greater than or equal to 50% reduction in mean sperm concentrations from

baseline at Week 26 (the primary endpoint). The difference between pregabalin and placebo was within

the pre-specified non-inferiority margin of 20%. There were no adverse effects of pregabalin on sperm

morphology, sperm motility, serum FSH or serum testosterone levels as compared to placebo. In

subjects in the PP population with greater than or equal to 50% reduction in sperm concentration from

baseline, sperm concentrations were no longer reduced by greater than or equal to 50% in any affected

subject after an additional 3 months off-drug. In one subject, however, subsequent semen analyses

demonstrated reductions from baseline of greater than or equal to 50% at 9 and 12 months off-drug. The

(0-24)

clinical relevance of these data is unknown.

In the animal fertility study with pregabalin in male rats, adverse reproductive and developmental effects

were observed [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Neuropathic Pain Associated with Diabetic Peripheral Neuropathy, Postherpetic Neuralgia, and

Neuropathic Pain Associated with Spinal Cord Injury

Safety and effectiveness in pediatric patients have not been established.

Fibromyalgia

Safety and effectiveness in pediatric patients have not been established.

Adjunctive Therapy for Partial-Onset Seizures

Safety and effectiveness in pediatric patients below the age of 1 month have not been established.

Juvenile Animal Data

In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the

postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in

learning and memory, altered locomotor activity, decreased auditory startle responding and habituation)

and reproductive impairment (delayed sexual maturation and decreased fertility in males and females)

were observed at doses greater than or equal to 50 mg/kg. The neurobehavioral changes of acoustic

startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze

performance at greater than or equal to 500 mg/kg in animals tested after cessation of dosing and, thus,

were considered to represent long-term effects. The low effect dose for developmental neurotoxicity

and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin

exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600

mg/day. A no-effect dose was not established.

Information describing a clinical study in which efficacy was not demonstrated in patients is approved for

Pfizer Inc.’s Lyrica (pregabalin) products. Additional pediatric use information is approved for Pfizer’s

LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer’s marketing exclusivity

rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

In controlled clinical studies of pregabalin in neuropathic pain associated with diabetic peripheral

neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older.

In controlled clinical studies of pregabalin in neuropathic pain associated with postherpetic neuralgia,

282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older.

In controlled clinical studies of pregabalin in epilepsy, there were only 10 patients 65 to 74 years of

age, and 2 patients who were 75 years of age or older.

No overall differences in safety and efficacy were observed between these patients and younger

patients.

In controlled clinical studies of pregabalin in fibromyalgia, 106 patients were 65 years of age or older.

Although the adverse reaction profile was similar between the two age groups, the following

neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness,

vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.

Pregabalin is known to be substantially excreted by the kidney, and the risk of toxic reactions to

pregabalin may be greater in patients with impaired renal function. Because pregabalin is eliminated

primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see Dosage and

Administration (2.7)].

8.6 Renal Impairment

Pregabalin is eliminated primarily by renal excretion and dose adjustment is recommended for adult

®

patients with renal impairment [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

The use of pregabalin in pediatric patients with compromised renal function has not been studied.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Pregabalin is a Schedule V controlled substance.

Pregabalin is not known to be active at receptor sites associated with drugs of abuse. As with any CNS

active drug, carefully evaluate patients for history of drug abuse and observe them for signs of

pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

9.2 Abuse

In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, pregabalin (450

mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that

was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4 %

of pregabalin-treated patients and 1 % of placebo-treated patients overall reported euphoria as an

adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged

from 1 to 12%.

9.3 Dependence

In clinical studies, following abrupt or rapid discontinuation of pregabalin, some patients reported

symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions (5.3)],

consistent with physical dependence. In the postmarketing experience, in addition to these reported

symptoms there have also been reported cases of anxiety and hyperhidrosis.

10 OVERDOSAGE

Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans

There is limited experience with overdose of pregabalin. The highest reported accidental overdose of

pregabalin during the clinical development program was 8000 mg, and there were no notable clinical

consequences.

Treatment or Management of Overdose

There is no specific antidote for overdose with pregabalin. If indicated, elimination of unabsorbed drug

may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General

supportive care of the patient is indicated including monitoring of vital signs and observation of the

clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the

management of overdose with pregabalin.

Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated

by the patient's clinical state or in patients with significant renal impairment. Standard hemodialysis

procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).

11 DESCRIPTION

Pregabalin, USP is described chemically as (S)-3-(aminomethyl)-5-methylhexanoic acid. The molecular

formula is C H NO and the molecular weight is 159.23. The chemical structure of pregabalin is:

Pregabalin, USP is a white to off-white, c rystalline solid with a p K of 4.2 and a pK of 10.6. It is

sparingly soluble in water. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at

pH 7.4 is – 1.35.

Pregabalin capsules are administered orally and are supplied as imprinted hard-shell capsules

containing 25, 50, 75, 100, 150, 200, 225, and 300 mg of pregabalin, USP, along with corn starch and

talc as inactive ingredients. The capsule shells contain gelatin and titanium dioxide. In addition, the

orange capsule shells contain red iron oxide which is used in 50 mg, 75 mg, 100 mg, 200 mg, 225 mg

and 300 mg strength of pregabalin capsules. The imprinting ink contains shellac, propylene glycol,

black iron oxide, and potassium hydroxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pregabalin binds with high affinity to the alpha -delta site (an auxiliary subunit of voltage-gated calcium

channels) in central nervous system tissues. Although the mechanism ofaction of pregabalin has not been

fully elucidated, results with genetically modified mice and with compounds structurally related to

pregabalin (such as gabapentin) suggest that binding to the alpha -delta subunit may be involved in

pregabalin's anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage,

pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in

the spinal cord, possibly by disrupting alpha -delta containing-calcium channel trafficking and/or

reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain

suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with

descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain

transmission in the spinal cord.

While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid

(GABA), it does not bind directly to GABA , GABA , or benzodiazepine receptors, does not augment

GABA responses in cultured neurons, does not alter rat brain GABA concentration or have acute

effects on GABA uptake or degradation. However, in cultured neurons prolonged application of

pregabalin increases the density of GABA transporter protein and increases the rate of functional

GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does

not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not

inhibit dopamine, serotonin, or noradrenaline reuptake.

12.3 Pharmacokinetics

Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an

elimination half-life of about 6 hours.

Absorption and Distribution

Following oral administration of pregabalin capsules under fasting conditions, peak plasma

concentrations occur within 1.5 hours. Pregabalin oral bioavailability is greater than or equal to 90%

and is independent of dose. Following single-(25 to 300 mg) and multiple-dose (75 to 900 mg/day)

administration, maximum plasma concentrations (C

) and area under the plasma concentration-time

curve (AUC) values increase linearly. Following repeated administration, steady state is achieved

within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.

The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in C

of approximately 25% to 30% and an increase in T

to approximately 3 hours. However,

administration of pregabalin with food has no clinically relevant effect on the total absorption of

pregabalin. Therefore, pregabalin can be taken with or without food.

Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin

following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L

transporter which is responsible for the transport of large amino acids across the blood brain barrier.

Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in

mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is

present in the milk of lactating rats.

Metabolism and Elimination

Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin,

approximately 90% of the administered dose was recovered in the urine as 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, pregabalin (S-enantiomer) did not undergo racemization to the

R-enantiomer in mice, rats, rabbits, or monkeys.

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug

with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal

clearance was estimated to be 67 to 80.9 mL/min in young healthy subjects. Because pregabalin is not

bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved.

Pregabalin elimination is nearly proportional to creatinine clearance (CLcr) [see Dosage and

Administration (2.7)].

Pharmacokinetics in Specific Populations

Race

In population pharmacokinetic analyses of the clinical studies in various populations, the

pharmacokinetics of pregabalin were not significantly affected by race (Caucasians, Blacks, and

Hispanics).

Gender

Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily

dose and pregabalin drug exposure is similar between genders.

Renal Impairment and Hemodialysis

Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients

with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis.

Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by

approximately 50%. For patients on hemodialysis, dosing must be modified [see Dosage and

Administration (2.7)].

Elderly

Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral

clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be

required in patients who have age-related compromised renal function [see Dosage and Administration

(2.7)].

Pediatric Pharmacokinetics

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution

products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that

pediatric information.

Drug Interactions

In Vitro Studies

Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not

inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme

systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or

CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g.

theophylline, caffeine) or CYP 3A4 substrates (e.g., midazolam, testosterone) is not anticipated.

In Vivo Studies

The drug interaction studies described in this section were conducted in healthy adults, and across

various patient populations.

Gabapentin

The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects

following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in

18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every 8

hours and 400-mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single-and

multiple-dose administration were unaltered by pregabalin coadministration. The extent of pregabalin

absorption was unaffected by gabapentin coadministration, although there was a small reduction in rate

of absorption.

Oral Contraceptive

Pregabalin coadministration (200 mg three times a day) had no effect on the steady-state

pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 μg, respectively) in healthy subjects.

Lorazepam

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the

rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam

(1 mg) had no effect on the steady-state pharmacokinetics of pregabalin.

Oxycodone

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the

rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone

(10 mg) had no effect on the steady-state pharmacokinetics of pregabalin.

Ethanol

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the

rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0.7

g/kg) had no effect on the steady-state pharmacokinetics of pregabalin.

Phenytoin, carbamazepine, valproic acid, and lamotrigine

Steady-state trough plasma concentrations of phenytoin, carbamazepine and carbamazepine 10,11

epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg three

times a day) administration.

Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant

medications suggest the following:

Therapeutic class Specific concomitant drug studied

Concomitant drug has no effect on the pharmacokinetics of pregabalin

Hypoglycemics Glyburide, insulin, metformin

Diuretics Furosemide

Antiepileptic Drugs Tiagabine

Concomitant drug has no effect on the pharmacokinetics of pregabalin and pregabalin has no effect on the pharmacokinetics of

concomitant drug

Antiepileptic Drugs Carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis,Mutagenesis, Impairment of Fertility

Carcinogenesis

A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was

observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the

diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased

hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose

(MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not

established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary

administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or

900 mg/kg in females) that were associated with plasma exposures in males and females up to

approximately 14 and 24 times, respectively, human exposure at the MRD.

Mutagenesis

Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in

mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat

hepatocytes.

Impairment of Fertility

In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to

and during mating with untreated females, a number of adverse reproductive and developmental effects

were observed. These included decreased sperm counts and sperm motility, increased sperm

abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased

fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility

parameters were reversible in studies of this duration (3 to 4 months). The no-effect dose for male

reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure

(AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600

mg/day.

In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were

observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four

weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250

mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD.

In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior

to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to

mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this

study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-

effect dose for female reproductive toxicity in rats was not established.

13.2 Animal Toxicology and/or Pharmacology

Dermatopathy

Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both

rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human

dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more

severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by

plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in

incidence of skin lesions was observed in clinical studies.

Ocular Lesions

Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal

inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats.

These findings were observed at plasma pregabalin exposures (AUC) greater than or equal to 2 times

those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for

ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity

studies in two strains of mice or in monkeys treated for 1 year.

14 CLINICAL STUDIES

14.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

The efficacy of the maximum recommended dose of pregabalin for the management of neuropathic pain

associated with diabetic peripheral neuropathy was established in three double-blind, placebo-

controlled, multicenter studies with three times a day dosing, two of which studied the maximum

recommended dose. Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a

diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years. A total of 89% of

patients completed Studies DPN 1 and DPN 2. The patients had a minimum mean baseline pain score

of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10

(worst possible pain). The baseline mean pain scores across the two studies ranged from 6.1 to 6.7.

Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to

pregabalin. Patients recorded their pain daily in a diary.

Study DPN 1: This 5-week study compared pregabalin 25, 100, or 200 mg three times a day with

placebo. Treatment with pregabalin 100 and 200 mg three times a day statistically significantly

improved the endpoint mean pain score and increased the proportion of patients with at least a 50%

reduction in pain score from baseline. There was no evidence of a greater effect on pain scores of the

200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose

dependent adverse reactions [see Adverse Reactions (6.1)]. For a range of levels of improvement in pain

intensity from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that level of

improvement. The figure is cumulative, so that patients whose change from baseline is, for example,

50%, are also included at every level of improvement below 50%. Patients who did not complete the

study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1,

which persisted throughout the study.

Figure 1: Patients Achieving Various Levels of Improvement in Pain Intensity – Study DPN 1

Study DPN 2: This 8-week study compared pregabalin 100 mg three times a day with placebo.

Treatment with pregabalin 100 mg three times a day statistically significantly improved the endpoint

mean pain score and increased the proportion of patients with at least a 50% reduction in pain score

from baseline. For various levels of improvement in pain intensity from baseline to study endpoint,

Figure 2 shows the fraction of patients achieving that level of improvement. The figure is cumulative,

so that patients whose change from baseline is, for example, 50%, are also included at every level of

improvement below 50%. Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 2: Patients Achieving Various Levels of Improvement in Pain Intensity– Study DPN 2

14.2 Postherpetic Neuralgia

The efficacy of pregabalin for the management of postherpetic neuralgia was established in three

double-blind, placebo-controlled, multicenter studies. These studies enrolled patients with neuralgia

persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score

of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10

(worst possible pain). Seventy-three percent of patients completed the studies. The baseline mean pain

scores across the 3 studies ranged from 6 to 7. Patients were permitted up to 4 grams of acetaminophen

per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.

Study PHN 1: This 13-week study compared pregabalin 75, 150, and 300 mg twice daily with placebo.

Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg,

or placebo twice daily. Patients with creatinine clearance greater than 60 mL/min were randomized to 75

mg, 150 mg, 300 mg or placebo twice daily. In patients with creatinine clearance greater than 60 mL/min

treatment with all doses of pregabalin statistically significantly improved the endpoint mean pain score

and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to

60 mL/min tolerated pregabalin less well than patients with creatinine clearance greater than 60 mL/min

as evidenced by higher rates of discontinuation due to adverse reactions. For various levels of

improvement in pain intensity from baseline to study endpoint, Figure 3 shows the fraction of patients

achieving that level of improvement. The figure is cumulative, so that patients whose change from

baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients

who did not complete the study were assigned 0% improvement. Some patients experienced a decrease

in pain as early as Week 1, which persisted throughout the study.

Figure 3: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 1

Study PHN 2: This 8-week study compared pregabalin 100 or 200 mg three times a day with placebo,

with doses assigned based on creatinine clearance. Patients with creatinine clearance between 30 to 60

mL/min were treated with 100 mg three times a day, and patients with creatinine clearance greater than

60 mL/min were treated with 200 mg three times daily. Treatment with pregabalin statistically

significantly improved the endpoint mean pain score and increased the proportion of patients with at

least a 50% reduction in pain score from baseline. For various levels of improvement in pain intensity

from baseline to study endpoint, Figure 4 shows the fraction of patients achieving those levels of

improvement. The figure is cumulative, so that patients whose change from baseline is, for example,

50%, are also included at every level of improvement below 50%. Patients who did not complete the

study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1,

which persisted throughout the study.

Figure 4: Patients Achieving Various Levels of Improvement in Pain Intensity – Study PHN 2

Study PHN 3: This 8-week study compared pregabalin 50 or 100 mg three times a day with placebo

with doses assigned regardless of creatinine clearance. Treatment with pregabalin 50 and 100 mg three

times a day statistically significantly improved the endpoint mean pain score and increased the

proportion of patients with at least a 50% reduction in pain score from baseline. Patients with creatinine

clearance between 30 to 60 mL/min tolerated pregabalin less well than patients with creatinine clearance

greater than 60 mL/min as evidenced by markedly higher rates of discontinuation due to adverse

reactions. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 5

shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that

patients whose change from baseline is, for example, 50%, are also included at every level of

improvement below 50%. Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 5: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 3

14.3 Adjunctive Therapy for Partial-Onset Seizures in Patients 17 Years of Age and Older

Adjunctive Therapy for Partial-Onset Seizures in Adult Patients

The efficacy of pregabalin as adjunctive therapy for partial-onset seizures in adult patients was

established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies.

Patients were enrolled who had partial-onset seizures with or without secondary generalization and

were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs). Patients taking

gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline. During

an 8-week baseline period, patients had to experience at least 6 partial-onset seizures with no seizure-

free period exceeding 4 weeks. The mean duration of epilepsy was 25 years in these 3 studies and the

mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively.

Approximately half of the patients were taking 2 concurrent AEDs at baseline. Among the pregabalin-

treated patients, 80% completed the double-blind phase of the studies.

Table 11 shows median baseline seizure rates and median percent reduction in seizure frequency by

dose.

Table 11. Seizure Response in Controlled, Adjunctive Epilepsy Studies in Adults

Daily Dose of

Pregabalin

Dos ing

Regimen

N

Baseline Seizure

Frequency/mo

Median %Change from

Baseline

p-value, vs.

placebo

Study E1

Placebo

50 mg/day

10.3

0.4230

150 mg/day

0.0001

300 mg/day

0.0001

600 mg/day

0.0001

Study E2

Placebo

150 mg/day

11.5

0.0007

600 mg/day

12.3

0.0001

Study E3

Placebo

BID/TID

600 mg/day

0.0001

600 mg/day

0.0001

In the first study (E1), there was evidence of a dose-response relationship for total daily doses of

pregabalin between 150 and 600 mg/day; a dose of 50 mg/day was not effective. In the first study (E1),

each daily dose was divided into two equal doses (twice a day dosing). In the second study (E2), each

daily dose was divided into three equal doses (three times a day dosing). In the third study (E3), the

same total daily dose was divided into two equal doses for one group (twice a day dosing) and three

equal doses for another group (three times a day dosing). While the three times a day dosing group in

Study E3 performed numerically better than the twice a day dosing group, this difference was small and

not statistically significant.

A secondary outcome measure included the responder rate (proportion of patients with greater than or

equal to 50% reduction from baseline in partial seizure frequency). The following figure displays

responder rate by dose for two of the studies.

Figure 6: Responder Rate by Adjunctive Epilepsy Study

Figure 7: Seizure Reduction by Dose (All Partial-Onset Seizures) for Studies E1, E2, and E3

Subset evaluations of the antiseizure efficacy of pregabalin showed no clinically important differences

as a function of age, gender, or race.

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution

products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that

pediatric information.

14.4 Management of Fibromyalgia

The efficacy of pregabalin for management of fibromyalgia was established in one 14-week, double-

blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2).

Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of

Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more

of the 18 specific tender point sites). The studies showed a reduction in pain by visual analog scale. In

addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the

Fibromyalgia Impact Questionnaire (FIQ).

Study F1: This 14-week study compared pregabalin total daily doses of 300 mg, 450 mg and 600 mg

with placebo. Patients were enrolled with a minimum mean baseline pain score of greater than or equal

to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100

mm pain visual analog scale (VAS). The baseline mean pain score in this trial was 6.7. Responders to

placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study. A

total of 64% of patients randomized to pregabalin completed the study. There was no evidence of a

greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was

evidence of dose-dependent adverse reactions [see Adverse Reactions (6.1)]. Some patients experienced

a decrease in pain as early as Week 1, which persisted throughout the study. The results are summarized

in Figure 9 and Table 14.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 9 shows the

fraction of patients achieving that level of improvement. The figure is cumulative. Patients who did not

complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as

early as Week 1, which persisted throughout the study.

Figure 9: Patients Achieving Various Levels of Improvement in Pain Intensity – Fibromyalgia Study F1

Table 14. Patient Global Response in Fibromyalgia Study F1

Patient Global Impression of Change

Treatment Group (mg/day)% Any Improvement 95% CI

Placebo

47.6

(40,55.2)

PGB 300

68.1

(60.9, 75.3)

PGB 450

77.8

(71.5, 84)

PGB 600

66.1

(59.1, 73.1)

PGB = Pregabalin

Study F2: This randomized withdrawal study compared pregabalin with placebo. Patients were titrated

during a 6-week open-label dose optimization phase to a total daily dose of 300 mg, 450 mg, or 600

mg. Patients were considered to be responders if they had both: 1) at least a 50% reduction in pain

(VAS) and, 2) rated their overall improvement on the PGIC as “much improved” or “very much

improved.” Those who responded to treatment were then randomized in the double-blind treatment phase

to either the dose achieved in the open-label phase or to placebo. Patients were treated for up to 6

months following randomization. Efficacy was assessed by time to loss of therapeutic response,

defined as 1) less than 30% reduction in pain (VAS) from open-label baseline during two consecutive

visits of the double-blind phase, or 2) worsening of FM symptoms necessitating an alternative treatment.

Fifty-four percent of patients were able to titrate to an effective and tolerable dose of pregabalin during

the 6-week open-label phase. Of the patients entering the randomized treatment phase assigned to remain

on pregabalin, 38% of patients completed 26 weeks of treatment versus 19% of placebo-treated

patients.

When considering return of pain or withdrawal due to adverse events as loss of response (LTR),

treatment with pregabalin resulted in a longer time to loss of therapeutic response than treatment with

placebo. Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients

remained on study drug and maintained a therapeutic response to Week 26 of the study. Treatment with

pregabalin also resulted in a longer time to loss of response based on the FIQ , and longer time to loss

of overall assessment of patient status, as measured by the PGIC .

Time to worsening of the FIQ was defined as the time to a 1-point increase from double-blind baseline

in each of the subscales, and a 5-point increase from double-blind baseline evaluation for the FIQ total

score.

Time to PGIC lack of improvement was defined as time to PGIC assessments indicating less

improvement than “much improvement.”

Figure 10: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier Analysis)

14.5 Management of Neuropathic Pain Associated with Spinal Cord Injury

The efficacy of pregabalin for the management of neuropathic pain associated with spinal cord injury

was established in two double-blind, placebo-controlled, multicenter studies. Patients were enrolled

with neuropathic pain associated with spinal cord injury that persisted continuously for at least three

months or with relapses and remissions for at least six months. A total of 63% of patients completed

study 1 and 84% completed study 2. The patients had a minimum mean baseline pain score of greater

than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst

possible pain). The baseline mean pain scores across the two studies ranged from 6.5 to 6.7.

Patients were allowed to take opioids, non-opioid analgesics, antiepileptic drugs, muscle relaxants, and

antidepressant drugs if the dose was stable for 30 days prior to screening. Patients were allowed to take

acetaminophen and nonsteroidal anti-inflammatory drugs during the studies.

Study SCI 1: This 12-week, randomized, double-blind, parallel-group, multicenter, flexible dose

(150to600 mg/day) study compared pregabalin with placebo. The 12-week study consisted of a 3-week

dose adjustment phase and a 9-week dose maintenance phase. Treatment with pregabalin 150 to 600

mg/day statistically significantly improved the endpoint weekly mean pain score, and increased the

proportion of patients with at least a 30% and 50% reduction in pain score from baseline. The fraction

of patients achieving various levels of improvement in pain intensity from baseline to Week 12 is

presented in Figure 11. Some patients experienced a decrease in pain as early as week 1, which

persisted throughout the study.

Figure 11: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 1

Study SCI 2: This 16-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter,

flexible dose (150 to 600 mg/day, in increments of 150 mg) study compared the efficacy, safety and

tolerability of pregabalin with placebo. The 16-week study consisted of a 4-week dose adjustment

phase and a 12-week dose maintenance phase. Treatment with pregabalin statistically significantly

improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a

30% and 50% reduction in pain score from baseline. The fraction of patients achieving various levels

of improvement in pain intensity from baseline to Week 16 is presented in Figure 12. Some patients

experienced a decrease in pain as early as week 1, which persisted throughout the study.

Figure12: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 2

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50090-4465

NDC: 50090-4465-0 90 CAPSULE in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Angioedema

Advise patients that pregabalin may cause angioedema, with swelling of the face, mouth (lip, gum,

tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct

patients to discontinue pregabalin and immediately seek medical care if they experience these symptoms

[see Warnings and Precautions (5.1)].

Hypersensitivity

Advise patients that pregabalin has been associated with hypersensitivity reactions such as wheezing,

dyspnea, rash, hives, and blisters. Instruct patients to discontinue pregabalin and immediately seek

medical care if they experience these symptoms [see Warnings and Precautions (5.2)].

Adverse Reactions with Abrupt or Rapid Discontinuation

Advise patients to take pregabalin as prescribed. Abrupt or rapid discontinuation may result in increased

seizure frequency in patients with seizure disorders, and insomnia, nausea, headache, anxiety,

hyperhidrosis, or diarrhea [see Warnings and Precautions (5.3)].

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including pregabalin, may

increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the

emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the

emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern

immediately to healthcare providers [see Warnings and Precautions (5.4)].

Dizziness and Somnolence

Counsel patients that pregabalin may cause dizziness, somnolence, blurred vision and other CNS signs

and symptoms. Accordingly, advise patients not to drive, operate complex machinery, or engage in other

hazardous activities until they have gained sufficient experience on pregabalin to gauge whether or not

it affects their mental, visual, and/or motor performance adversely [see Warnings and Precautions (5.6)].

Weight Gain and Edema

Counsel patients that pregabalin may cause edema and weight gain. Advise patients that concomitant

treatment with pregabalin and a thiazolidinedione antidiabetic agent may lead to an additive effect on

edema and weight gain. For patients with preexisting cardiac conditions, this may increase the risk of

heart failure [see Warnings and Precautions (5.5 and 5.7)].

Ophthalmological Effects

Counsel patients that pregabalin may cause visual disturbances. Inform patients that if changes in vision

occur, they should notify their physician [see Warnings and Precautions (5.9)].

Creatine Kinase Elevations

Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if

accompanied by malaise or fever [see Warnings and Precautions (5.10)].

CNS Depressants

Inform patients who require concomitant treatment with central nervous system depressants such as

opiates or benzodiazepines that they may experience additive CNS side effects, such as somnolence

[see Warnings and Precautions (5.6) and Drug Interactions (7)].

Alcohol

Tell patients to avoid consuming alcohol while taking pregabalin, as pregabalin may potentiate the

impairment of motor skills and sedating effects of alcohol.

Missed Dose

Counsel patients if they miss a dose, they should take it as soon as they remember. If it is almost time for

the next dose, they should skip the missed dose and take the next dose at their regularly scheduled time.

Instruct patients not to take two doses at the same time.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to

pregabalin during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise nursing mothers that breastfeeding is not recommended during treatment with pregabalin[see Use

in Specific Populations (8.2)].

Male Fertility

Inform men being treated with pregabalin who plan to father a child of the potential risk of male-

mediated teratogenicity. In preclinical studies in rats, pregabalin was associated with an increased risk

of male-mediated teratogenicity. The clinical significance of this finding is uncertain [see Nonclinical

Toxicology (13.1)and Use in Specific Populations (8.3)].

Dermatopathy

Instruct diabetic patients to pay particular attention to skin integrity while being treated with pregabalin

and to inform their healthcare provider about any sores or skin problems. Some animals treated with

pregabalin developed skin ulcerations, although no increased incidence of skin lesions associated with

pregabalin was observed in clinical trials [see Nonclinical Toxicology (13.2)].

Medication Guide available at http://www.alembicusa.com/medicationguide.aspx or call 1-866-210-

Medication Guide available at http://www.alembicusa.com/medicationguide.aspx or call 1-866-210-

9797.

Manufactured by:

Alembic Pharmaceuticals Limited

(Formulation Division),

Panelav 389350, Gujarat, India

Manufactured for:

Alembic Pharmaceuticals, Inc.

750 Route 202, Bridgewater, NJ 08807

Revised: 07/2019

Medication Guide

Pregabalin (pree-GAH-ba-lin)

Capsules, CV

Read this Medication Guide before you start taking pregabalin and each time you get a refill. There may

be new information. This information does not take the place of talking to your healthcare provider

about your medical condition or treatment. If you have any questions about pregabalin, ask your

healthcare provider or pharmacist.

What is the most important information I should know about pregabalin?

Pregabalin may cause serious side effects including:

serious, even life-threatening, allergic reactions swelling of your hands, legs and feet

suicidal thoughts or actions

dizziness and sleepiness

These serious side effects are described below:

· Serious, even life-threatening, allergic reactions.

Stop taking pregabalin and call your healthcare provider right away if you have any of these signs of a

serious allergic reaction:

o swelling of your face, mouth, lips, gums, tongue, throat or neck

o trouble breathing

o rash, hives (raised bumps) or blisters

· Like other antiepileptic drugs, pregabalin may cause suicidal thoughts or actions in a very

small number of people, about 1 in 500. Call a healthcare provider right away if you have any of

these symptoms, especially if they are new, worse, or worry you:

o thoughts about suicide or dyingo trouble sleeping (insomnia)

o attempts to commit suicide

o new or worse irritability

o new or worse depression

o acting aggressive, being angry, or violent

o new or worse anxiety

o acting on dangerous impulses

o feeling agitated or restless

o an extreme increase in activity and talking (mania)

o panic attacks

o other unusual changes in behavior or mood

If you have suicidal thoughts or actions, do not stop pregabalin without first talking to a

healthcare provider.

Stopping pregabalin suddenly can cause serious problems.

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal

thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about

symptoms.

· Swelling of your hands, legs and feet. This swelling can be a serious problem for people with

heart problems.

· Dizziness and sleepiness. Do not drive a car, work with machines, or do other dangerous

activities until you know how pregabalin affects you. Ask your healthcare provider about when it will

be okay to do these activities.

What is pregabalin?

Pregabalin is a prescription medicine used in adults, 18 years of age and older to treat:

pain from damaged nerves (neuropathic pain) that happens with diabetes

pain from damaged nerves (neuropathic pain) that follows healing of shingles

fibromyalgia (pain all over your body)

pain from damaged nerves (neuropathic pain) that follows spinal cord injury

It is not known if pregabalin is safe and effective in people under 18 years of age for the treatment of

fibromyalgia and neuropathic pain with diabetes, shingles, or spinal cord injury.

Pregabalin is a prescription medicine used in people 17 years of age and older to treat:

partial-onset seizures when taken together with other seizure medicines.

For the treatment of partial-onset seizures when taken together with other seizure medicines, it is not

known if pregabalin is safe and effective in children under 1 month of age.

Who should not take pregabalin?

Do not take pregabalin capsules if you are allergic to pregabalin or any of the ingredients in

pregabalin capsules.

See “What is the most important information I should know about pregabalin?” for the signs of an

allergic reaction.

See the end of this Medication Guide for a complete list of ingredients in pregabalin.

What should I tell my healthcare provider before taking pregabalin?

Before taking pregabalin, tell your healthcare provider about all your medical conditions, including if

you:

· have or have had depression, mood problems or suicidal thoughts or behavior.

· have kidney problems or get kidney dialysis.

· have heart problems including heart failure.

· have a bleeding problem or a low blood platelet count.

· have abused prescription medicines, street drugs, or alcohol in the past.

· have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema).

· plan to father a child. Animal studies have shown that pregabalin, the active ingredient in

pregabalin, made male animals less fertile and caused sperm to change. Also, in animal studies, birth

defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if

these problems can happen in people who take pregabalin.

· are pregnant or plan to become pregnant. Pregabalin may harm your unborn baby. You

and your healthcare provider will decide if you should take pregabalin while you are pregnant.

o If you become pregnant while taking pregabalin, talk to your healthcare provider about registering

with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by

calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of

antiepileptic drugs during pregnancy. Information about the registry can also be found at the web site,

http://www.aedpregnancyregistry.org/.

· are breastfeeding or plan to breastfeed. Pregabalin passes into your breast milk. It is not

known if pregabalin can harm your baby. Talk to your healthcare provider about the best way to feed

your baby if you take pregabalin. Breastfeeding is not recommended while taking pregabalin.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins or herbal supplements. Pregabalin and other medicines may affect each

other causing side effects. Especially tell your healthcare provider if you take:

· angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions,

including high blood pressure. You may have a higher chance for swelling and hives if these medicines

are taken with pregabalin.

Avandia (rosiglitazone) or Actos (pioglitazone) for diabetes. You may have a higher chance of

weight gain or swelling of your hands or feet if these medicines are taken with pregabalin.

· any narcotic pain medicine (such as oxycodone), tranquilizers or medicines for anxiety (such as

lorazepam). You may have a higher chance for dizziness and sleepiness if these medicines are taken

with pregabalin.

· any medicines that make you sleepy.

Know the medicines you take. Keep a list of them with you to show your healthcare provider and

pharmacist each time you get a new medicine. Do not start a new medicine without talking with your

healthcare provider.

How should I take pregabalin?

· Take pregabalin exactly as prescribed. Your healthcare provider will tell you how much

pregabalin to take and when to take it.

· Pregabalin may be taken with or without food.

· Your healthcare provider may change your dose. Do not change your dose without talking to your

healthcare provider.

· Do not stop taking pregabalin without talking to your healthcare provider. If you stop taking

pregabalin suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or

you may feel anxious. If you have epilepsy and you stop taking pregabalin suddenly, you may have

seizures more often. Talk with your healthcare provider about how to stop pregabalin slowly.

· If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, just

skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time.

· If you take too much pregabalin, call your healthcare provider or poison control center, or go to

the nearest emergency room right away.

What should I avoid while taking pregabalin?

· Do not drive a car, work with machines, or do other dangerous activities until you know

how pregabalin affects you.

· Do not drink alcohol while taking pregabalin. Pregabalin and alcohol can affect each other and

increase side effects such as sleepiness and dizziness.

What are the possible side effects of pregabalin?

Pregabalin may cause serious side effects, including:

· See “What is the most important information I should know about pregabalin?"

· Muscle problems, muscle pain, soreness, or weakness. If you have these symptoms,

especially if you feel sick and have a fever, tell your healthcare provider right away.

· Problems with your eyesight, including blurry vision. Call your healthcare provider if you

have any changes in your eyesight.

· Weight gain. If you have diabetes, weight gain may affect the management of your diabetes.

Weight gain can also be a serious problem for people with heart problems.

· Feeling "high".

The most common side effects of pregabalin are:

dizziness

weight gain trouble concentrating

blurry vision sleepiness swelling of hands and feet

dry mouth

Pregabalin caused skin sores in animal studies. Skin sores did not happen in studies in people. If you

have diabetes, you should pay attention to your skin while taking pregabalin and tell your healthcare

provider about any sores or skin problems.

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of pregabalin. For more information, ask your healthcare

provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store pregabalin?

· Store pregabalin capsul e at 25 °C (77°F); e xcursions pe r mitted to 15°C to 30°C (59°F to 86°F)

(see USP Controlled Room T e m perature) in its o riginal package.

· Safely throw away any pregabalin that is out of date or no longer needed.

Keep pregabalin and all medicines out of the reach of children.

General information about the safe and effective use of pregabalin

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use pregabalin for a condition for which it was not prescribed. Do not give pregabalin to other people,

even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider

or pharmacist for information about pregabalin that is written for health professionals.

For more information call Alembic Pharmaceuticals Limited at 1-866-210-9797.

What are the ingredients in pregabalin?

Active i ng re die nt: pre ga balin

Inactive ingredients: corn starch and talc

The caps ule shells contain gelatin and titanium dioxide. In addition, the orange capsule shells contain

red iron oxide which is used in 50 mg, 75 mg, 100 mg, 200 mg, 225 mg and 300 mg strength of

pregabalin capsules. The i mprinting ink contains shellac, propylene glycol, black iron oxide, and

potassium hydroxide.

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution

products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that

pediatric information.

This Medication Guide has been approved by t he U.S. Food and Drug A dm in istration.

Trademarks are the property of their respective owners.

Medication Guide available at http://www.alembicusa.com/medicationguide.aspx or call 1-866-210-

9797.

Manufactured by:

Alembic Pharmaceuticals Limited

(Formulation Division),

Panelav 389350, Gujarat, India

Manufactured for:

Alembic Pharmaceuticals, Inc.

750 Route 202, Bridgewater, NJ 08807

Revised: 07/2019

Pregabalin

PREGABALIN

pregabalin capsule

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 0 9 0 -

446 5(NDC:6 2332-121)

Route of Administration

ORAL

DEA Sche dule

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

PREGABALIN (UNII: 55JG375S6 M) (PREGABALIN - UNII:55JG375S6 M)

PREGABALIN

75 mg

Inactive Ingredients

Ingredient Name

Stre ng th

STARCH, CO RN (UNII: O8 232NY3SJ)

TALC (UNII: 7SEV7J4R1U)

GELATIN, UNSPECIFIED (UNII: 2G8 6 QN327L)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

Product Characteristics

Color

WHITE (Opaque white) , ORANGE (Orange o paque)

S core

no sco re

S hap e

CAPSULE

S iz e

14mm

Flavor

Imprint Code

A;142

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 0 9 0 -446 5-0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /13/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

A-S Medication Solutions

ANDA

ANDA20 3459

0 7/19 /20 19

Labeler -

A-S Medication Solutions (830016429)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

A-S Medicatio n So lutio ns

8 30 0 16 429

RELABEL(50 0 9 0 -446 5)

Revised: 8/2019

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