LYRICA- pregabalin capsule

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

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Active ingredient:
PREGABALIN (UNII: 55JG375S6M) (PREGABALIN - UNII:55JG375S6M)
Available from:
Dispensing Solutions, Inc.
INN (International Name):
PREGABALIN
Composition:
PREGABALIN 75 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
LYRICA is indicated for: - Management of neuropathic pain associated with diabetic peripheral neuropathy - Management of postherpetic neuralgia - Adjunctive therapy for adult patients with partial onset seizures - Management of fibromyalgia - Management of neuropathic pain associated with spinal cord injury LYRICA 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. Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. When pregnant rats were given pregabalin (500, 1250, or 2
Product summary:
75 mg capsules: White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 75" on the body; available in: Bottles of 90: NDC 68258-7980-09 Storage and Handling Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature). See FDA-Approved Medication Guide
Authorization status:
New Drug Application
Authorization number:
68258-7980-9

LYRICA- pregabalin capsule

Dispensing Solutions, Inc.

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MEDICATION GUIDE

LYRICA (LEER-i-kah)

(pregabalin)

Capsules and Oral Solution, CV

Read this Medication Guide before you start taking LYRICA 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 LYRICA, ask your healthcare

provider or pharmacist.

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

LYRICA may cause serious side effects including:

Serious, even life-threatening, allergic reactions

Suicidal thoughts or actions

Swelling of your hands, legs and feet

Dizziness and sleepiness

These serious side effects are described below:

Serious, even life-threatening, allergic reactions.

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

a serious allergic reaction:

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

trouble breathing

rash, hives (raised bumps) or blisters

Like other antiepileptic drugs, LYRICA 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:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

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

provider.

Stopping LYRICA 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

LYRICA affects you. Ask your healthcare provider about when it will be okay to do these activities.

What is LYRICA?

LYRICA is a prescription medicine used in adults, 18 years 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

partial seizures when taken together with other seizure medicines

fibromyalgia (pain all over your body)

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

LYRICA has not been studied in children under 18 years of age.

Who Should Not Take LYRICA?

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

See "What is the most important information I should know about LYRICA?" for the signs of an allergic

reaction.

See the end of this leaflet for a complete list of ingredients in LYRICA.

What should I tell my healthcare provider before taking LYRICA?

Before taking LYRICA, 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

LYRICA, 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 LYRICA.

are pregnant or plan to become pregnant. It is not known if LYRICA will harm your unborn baby.

You and your healthcare provider will have to decide if you should take LYRICA while you are

pregnant. If you become pregnant while taking LYRICA, 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.

are breastfeeding. It is not known if LYRICA passes into breast milk and if it can harm your baby.

You and your healthcare provider should discuss whether you should take LYRICA or breast-

feed, but you should not do both

Tell your healthcare provider about all the medicines you take including prescription and non-prescription

medicines, vitamins or herbal supplements. LYRICA 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 LYRICA. See "What is the most important information I should know

about LYRICA?"

Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), 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 LYRICA. See "What are the possible side effects

of LYRICA."

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 LYRICA.

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 LYRICA?

Take LYRICA exactly as prescribed. Your healthcare provider will tell you how much LYRICA

to take and when to take it. Take LYRICA at the same times each day.

LYRICA 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 LYRICA without talking to your healthcare provider. If you stop taking

LYRICA suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased

sweating, or you may feel anxious. If you have epilepsy and you stop taking LYRICA suddenly,

you may have seizures more often. Talk with your healthcare provider about how to stop LYRICA

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 LYRICA, call your healthcare provider or poison control center, or go to the

nearest emergency room right away.

What should I avoid while taking LYRICA?

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

LYRICA affects you.

Do not drink alcohol while taking LYRICA. LYRICA and alcohol can affect each other and

increase side effects such as sleepiness and dizziness.

What are the possible side effects of LYRICA?

LYRICA may cause serious side effects, including:

See "What is the most important information I should know about LYRICA?"

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 LYRICA are:

dizziness

blurry vision

weight gain

sleepiness

trouble concentrating

swelling of hands and feet

dry mouth

LYRICA 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 LYRICA 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 LYRICA. 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 LYRICA?

Store LYRICA capsules and oral solution at room temperature, 59°F to 86°F (15°C to 30°C) in its

original package.

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

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

General information about LYRICA

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

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

if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about LYRICA. If you would like

more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist

for information about LYRICA that is written for health professionals.

You can also visit the LYRICA website at www.LYRICA.com or call 1-866-459-7422 (1-866-

4LYRICA).

What are the ingredients In LYRICA?

Active ingredient: pregabalin

Inactive ingredients:

LYRICA capsules: lactose monohydrate, cornstarch, talc

Capsule shell: gelatin and titanium dioxide; Orange capsule shell: red iron oxide; White capsule shell:

sodium lauryl sulfate, colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may

or may not be present in the capsule shells.

Imprinting ink: shellac, black iron oxide, propylene glycol, potassium hydroxide.

LYRICA oral solution: methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic

sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 7/2013

Document Id: 04ac4476-c8ce-4c16-a8d5-484492d52c5d

Set id: 869d4092-6980-48b3-abc8-37bf3e5a9510

Version: 1

Effective Time: 20130729

Dispensing Solutions, Inc.

LYRICA- pregabalin capsule

Dispensing Solutions, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LYRICA safely and effectively. See full

prescribing information for LYRICA.

LYRICA (pregabalin) Capsules, CV

LYRICA (pregabalin) Oral Solution, CV

Initial U.S. Approval: 2004

RECENT MAJOR CHANGES

Indications and Usage (1)

6/2012

Dosage and Administration (2.5)

6/2012

Warnings and Precautions (5.6)

6/2012

Warnings and Precautions (5.8)

6/2012

INDICATIONS AND USAGE

LYRICA is indicated for:

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

Postherpetic neuralgia (PHN) (1)

Adjunctive therapy for adult patients with partial onset seizures (1)

Fibromyalgia (1)

Neuropathic pain associated with spinal cord injury (1)

DOSAGE AND ADMINISTRATION

For all indications, begin dosing at 150 mg/day. (2.1, 2.2, 2.3, 2.4, 2.5)

Dosing recommendations:

INDICATION

Dosing Regimen

Maximum Dose

DPN Pain (2.1)

3 divided doses per day

300 mg/day within 1

week

PHN (2.2)

2 or 3 divided doses per

300 mg/day within 1

week. Maximum dose

of 600 mg/day.

Adjunctive Therapy for

Adult Patients with

Partial Onset Seizures

(2.3)

2 or 3 divided doses per

Maximum dose of 600

mg/day.

Fibromyalgia (2.4)

2 divided doses per day

300 mg/day within 1

we e k.

Maximum dose of 450

mg/day.

Neuropathic Pain

Associated with Spinal

Cord Injury (2.5)

2 divided doses per day

300 mg/day within 1

week. Maximum dose

of 600 mg/day.

Dose should be adjusted in patients with reduced renal function. (2.6)

Oral Solution Concentration and Dispensing (2.7)

DOSAGE FORMS AND STRENGTHS

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

Oral Solution: 20 mg/ mL. (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 LYRICA immediately in these cases. (5.1)

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

patients. (5.2)

Increased seizure frequency may occur in patients with seizure disorders if LYRICA is rapidly discontinued. Withdraw

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

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

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

antidiabetic agents. (5.5)

LYRICA may cause dizziness and somnolence and impair patients' ability to drive or operate machinery.(5.6)

ADVERSE REACTIONS

Most common adverse reactions (≥ 5% and twice placebo) 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 Pfizer at (800) 438-1985 or FDA at 1-800-FDA-1088 or

www.fda.g o v/medwatch

USE IN SPECIFIC POPULATIONS

To enroll in the North American Antiepileptic Drug Pregnancy Registry call 1-888-233-2334 (toll free). (8.1 )

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 7/2013

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

2.2 Postherpetic Neuralgia

2.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures

2.4 Management of Fibromyalgia

2.5 Neuropathic Pain Associated with Spinal Cord Injury

2.6 Patients with Renal Impairment

2.7 Oral Solution Concentration and Dispensing

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Angioedema

5.2 Hypersensitivity

5.3 Withdrawal of Antiepileptic Drugs (AEDs)

5.4 Suicidal Behavior and Ideation

5.5 Peripheral Edema

5.6 Dizziness and Somnolence

5.7 Weight Gain

5.8 Abrupt or Rapid Discontinuation

5.9 Tumorigenic Potential

5.10 Ophthalmological Effects

5.11 Creatine Kinase Elevations

5.12 Decreased Platelet Count

5.13 PR Interval Prolongation

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

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 Adult Patients with Partial Onset Seizures

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

17.1 Medication Guide

17.2 Angioedema

17.3 Hypersensitivity

17.4 Suicidal Thinking and Behavior

17.5 Dizziness and Somnolence

17.6 Weight Gain and Edema

17.7 Abrupt or Rapid Discontinuation

17.8 Ophthalmological Effects

17.9 Creatine Kinase Elevations

17.10 CNS Depressants

17.11 Alcohol

17.12 Use in Pregnancy

17.13 Male Fertility

17.14 Dermatopathy

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

LYRICA is indicated for:

Management of neuropathic pain associated with diabetic peripheral neuropathy

Management of postherpetic neuralgia

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

Adjunctive therapy for adult patients with partial onset seizures

Management of fibromyalgia

Management of neuropathic pain associated with spinal cord injury

2 DOSAGE AND ADMINISTRATION

LYRICA is given orally with or without food.

When discontinuing LYRICA, taper gradually over a minimum of 1 week.

2.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

The maximum recommended dose of LYRICA 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. Because

LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal

function [see Dosage and Administration (2.6)].

Although LYRICA 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)].

2.2 Postherpetic Neuralgia

The recommended dose of LYRICA 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. Because LYRICA is eliminated primarily by renal

excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6)].

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 LYRICA, 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)].

2.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures

LYRICA at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the

treatment of partial onset seizures in adults. Both the efficacy and adverse event profiles of LYRICA

have been shown to be dose-related. Administer the total daily dose in two or three divided doses. In

general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75

mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability,

the dose may be increased to a maximum dose of 600 mg/day.

Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced

renal function [see Dosage and Administration (2.6)].

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

The efficacy of add-on LYRICA in patients taking gabapentin has not been evaluated in controlled trials.

Consequently, dosing recommendations for the use of LYRICA with gabapentin cannot be offered.

2.4 Management of Fibromyalgia

The recommended dose of LYRICA 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 LYRICA 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)]. Because LYRICA is eliminated primarily by

renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration

(2.6)].

2.5 Neuropathic Pain Associated with Spinal Cord Injury

The recommended dose range of LYRICA 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 LYRICA may be treated with up to 300 mg two

times a day [see Clinical Studies (14.5)]. Because LYRICA is eliminated primarily by renal excretion,

adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6)].

2.6 Patients with Renal Impairment

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

excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients

with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. 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 ≥60 mL/min). Then refer to Table 1

to determine the corresponding renal adjusted dose.

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

(CLcr ≥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 1).

Table 1. Pregabalin Dosage Adjustment Based on Renal Function

Creatinine Clearance

(CLcr)

(mL/min)

Total Pregabalin Daily Dose

(mg/day)

Dose Regimen

≥60

BID or TID

30–60

BID or TID

15–30

25–50

100–150

QD or BID

<15

25–50

50–75

Supplementary dosage following hemodialysis (mg)

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

*

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

dose.

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

or 75 mg

Patients on the 50–75 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

2.7 Oral Solution Concentration and Dispensing

The oral solution is 20 mg pregabalin per milliliter (mL) and prescriptions should be written in

milligrams (mg). The pharmacist will calculate the applicable dose in mL for dispensing (e.g., 150 mg

equals 7.5 mL oral solution).

3 DOSAGE FORMS AND STRENGTHS

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

Oral Solution: 20 mg/mL

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

4 CONTRAINDICATIONS

LYRICA 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.

5 WARNINGS AND PRECAUTIONS

5.1 Angioedema

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

with LYRICA. 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 LYRICA immediately in patients with these

symptoms.

Exercise caution when prescribing LYRICA 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

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

Discontinue LYRICA immediately in patients with these symptoms.

5.3 Withdrawal of Antiepileptic Drugs (AEDs)

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

mg/dose.

Supplementary dose is a single additional dose.

As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure

frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a

minimum of 1 week.

5.4 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including LYRICA, 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 (5–100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2. 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

Ris k

Difference:

Additional

Drug

Patients with

Events 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 LYRICA 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 be related to the

illness being treated.

Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal

thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the

signs and 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.

5.5 Peripheral Edema

LYRICA 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 the incidence of peripheral edema was 6% in the LYRICA group compared

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

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 LYRICA only, and 19% (23/120) of patients who were on

both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0%

(0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA 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 LYRICA 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 LYRICA in these patients.

5.6 Dizziness and Somnolence

LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and

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

Counseling Information (17.5)].

In the LYRICA controlled trials, dizziness was experienced by 30% of LYRICA-treated patients

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

patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly

after the initiation of LYRICA 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 LYRICA-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)].

5.7 Weight Gain

LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a

gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of

placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due

to weight gain. LYRICA 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 LYRICA-associated weight gain are

unknown.

Among diabetic patients, LYRICA-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 LYRICA for at least 2 years, the average weight gain was 5.2 kg.

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

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

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

5.8 Abrupt or Rapid Discontinuation

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

insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. Taper LYRICA gradually over a

minimum of 1 week rather than discontinuing the drug abruptly.

5.9 Tumorigenic Potential

In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, 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

LYRICA'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 >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 LYRICA,

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

5.10 Ophthalmological Effects

In controlled studies, a higher proportion of patients treated with LYRICA 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 LYRICA 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 LYRICA, and 5% of placebo-treated patients. Visual

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

Funduscopic changes were observed in 2% of LYRICA-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 (17.8)].

5.11 Creatine Kinase Elevations

LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from

baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo

patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and

0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal.

Three LYRICA treated subjects had events reported as rhabdomyolysis in premarketing clinical trials.

The relationship between these myopathy events and LYRICA 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 LYRICA if myopathy is

diagnosed or suspected or if markedly elevated creatine kinase levels occur.

5.12 Decreased Platelet Count

LYRICA treatment was associated with a decrease in platelet count. LYRICA-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, 2% of placebo patients and 3% of LYRICA

patients experienced a potentially clinically significant decrease in platelets, defined as 20% below

baseline value and <150 × 10 /µL. A single LYRICA treated subject developed severe

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

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

5.13 PR Interval Prolongation

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

the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change

difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased

percentage of subjects with on-treatment PR >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

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 LYRICA, more than 10,000 patients have received LYRICA. 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 populations combined, 14% of patients treated with LYRICA and

7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA

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 <1%

withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials

more frequently in the LYRICA 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 Premarketing Controlled Clinical Studies

In premarketing controlled trials of all patient populations combined, 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 LYRICA than by

subjects treated with placebo (≥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 patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of

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

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

adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients

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

with greater frequency in the LYRICA 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 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with

neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the

incidence was greater in this combined LYRICA 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 3. Treatment-emergent adverse reaction incidence in controlled trials in

neuropathic pain associated with diabetic peripheral neuropathy (events in at least

1% of all LYRICA-treated patients and at least numerically more in all LYRICA

than in the placebo group)

Body system

Preferred term

75

mg/day

150

mg/day

300

mg/day

600

mg/day

All PGB

Placebo

[N=77]

%

[N=212]

%

[N=321]

%

[N=369]

%

[N=979]

%

[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

Controlled Studies in Postherpetic Neuralgia

Adverse Reactions Leading to Discontinuation

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

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

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

LYRICA 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 4 lists all adverse reactions, regardless of causality, occurring in ≥ 1% of patients with

neuropathic pain associated with postherpetic neuralgia in the combined LYRICA group for which the

incidence was greater in this combined LYRICA group than in the placebo group. In addition, an event is

included, even if the incidence in the all LYRICA 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 9.0% 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 4. Treatment-emergent adverse reaction incidence in controlled trials in

neuropathic pain associated with postherpetic neuralgia (events in at least 1% of

all LYRICA-treated patients and at least numerically more in all LYRICA than in

the placebo group)

Body system

Preferred term

75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB

Placebo

[N=84]

%

[N=302]

%

[N=312]

%

[N=154]

%

[N=852]

%

[N=398]

%

Body as a whole

Infection

Headache

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

*

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

Controlled Add-On Studies in Adjunctive Therapy for Adult Patients with Partial Onset Seizures

Adverse Reactions Leading to Discontinuation

Approximately 15% of patients receiving LYRICA and 6% of patients receiving placebo in add-on

epilepsy trials discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the

adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and

somnolence (3%). In comparison, <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 LYRICA

group and at least twice as frequently compared to the placebo group were asthenia, diplopia, blurred

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

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 5 lists all dose-related adverse reactions occurring in at least 2% of all LYRICA-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 LYRICA and 294 patients received placebo for up to 12 weeks. Because patients were also

treated with 1 to 3 other AEDs, it is not possible to determine whether the following adverse reactions

can be ascribed to LYRICA alone, or the combination of LYRICA and other AEDs. A majority of

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

or "moderate".

Table 5. Dose-related treatment-emergent adverse reaction incidence in controlled

trials in adjunctive therapy for adult patients with partial onset seizures (events in

at least 2% of all LYRICA-treated patients and the adverse reaction in the 600

mg/day group was ≥2% the rate in both the placebo and 150 mg/day groups)

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 Disorders

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

Controlled Studies with Fibromyalgia

Adverse Reactions Leading to Discontinuation

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

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, <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 6 lists all adverse reactions, regardless of causality, occurring in ≥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 6. Treatment-emergent adverse reaction incidence in controlled trials in

fibromyalgia (events) in at least 2% of all LYRICA-treated patients and occurring

more frequently in the all pregabalin-group than in the placebo treatment group)

System Organ Class

Preferred term

150

mg/d

300

mg/d

450

mg/d

600

mg/d

All PGB

Placebo

[N=132]

%

[N=502]

%

[N=505]

%

[N=378]

%

[N=1517]

%

[N=505]

%

Ear and Labyrinth

Dis orders

Vertigo

Eye Disorders

Vision blurred

Gastrointestinal

Dis orders

Dry mouth

Constipation

Vomiting

Flatulence

Abdominal distension

General Disorders and

Administrative Site

Conditions

Fatigue

Edema peripheral

Chest pain

Feeling abnormal

Edema

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.

*

Feeling drunk

Infections and

Infes tations

Sinusitis

Inves tigations

Weight increased

Metabolism and

Nutrition Disorders

Increased appetite

Fluid retention

Musculoskeletal and

Connective Tissue

Dis orders

Arthralgia

Muscle spasms

Back pain

Nervous System

Dis orders

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

Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury

Adverse Reactions Leading to Discontinuation

In clinical trials of patients 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

PGB: pregabalin

patients.

Most Common Adverse Reactions

Table 7 lists all adverse reactions, regardless of causality, occurring in ≥2% of patients 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 7. Treatment-emergent adverse reaction incidence in controlled

trials in neuropathic pain associated with spinal cord injury (events in at

least 2% of all LYRICA-treated patients and occurring more frequently

in the all pregabalin-group than in the placebo treatment group)

System Organ Class

Preferred term

PGB (N=182)

Placebo (N=174)

%

%

Ear and labryrinth disorders

Vertigo

Eye disorders

Vision blurred

Gastrointestinal disorders

Dry mouth

11.0

Constipation

Nausea

Vomiting

General disorders and

administration site conditions

Fatigue

11.0

Edema peripheral

10.4

Edema

Pain

Infections and infestations

Nasopharyngitis

Inves tigations

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

Other Adverse Reactions Observed During the Clinical Studies of LYRICA

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

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

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

PGB: Pregabalin

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.

6.2 Post-marketing Experience

The following adverse reactions have been identified during postapproval use of LYRICA. 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 post-marketing reports of events related to reduced lower gastrointestinal tract

function (e.g., intestinal obstruction, paralytic ileus, constipation) when LYRICA was co-administered

with medications that have the potential to produce constipation, such as opioid analgesics. There are

also post-marketing reports of respiratory failure and coma in patients taking pregabalin and other CNS

depressant medications.

7 DRUG INTERACTIONS

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

humans (<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 LYRICA 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 LYRICA and commonly used antiepileptic drugs [see Clinical Pharmacology

(12)].

Pharmacodynamics

Multiple oral doses of LYRICA 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 LYRICA was co-administered with these drugs. No clinically important

effects on respiration were seen.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations

of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system

functional impairment, were observed in the offspring of rats and rabbits given pregabalin during

pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the

maximum recommended dose (MRD) of 600 mg/day.

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 ≥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 LYRICA (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 LYRICA (50, 100, 250, 1250, or 2500 mg/kg)

throughout gestation and lactation, offspring growth was reduced at ≥ 100 mg/kg and offspring survival

was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥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 ≥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.

There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy

only if the potential benefit justifies the potential risk to the fetus.

To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised

to recommend that pregnant patients taking LYRICA 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/.

8.2 Labor and Delivery

The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal

study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean

human exposure (AUC

of 123 µg·hr/mL) at the maximum recommended clinical dose of 600

mg/day.

8.3 Nursing Mothers

It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats.

Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown

for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking

into account the importance of the drug to the mother.

(0–24)

8.4 Pediatric Use

The safety and efficacy of pregabalin in pediatric patients have not been established.

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 ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250

mg/kg and locomotor activity and water maze performance at ≥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.

8.5 Geriatric Use

In controlled clinical studies of LYRICA 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 LYRICA 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 LYRICA 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 LYRICA 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.

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

may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by

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

Administration (2.6)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

LYRICA is a Schedule V controlled substance.

LYRICA 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

LYRICA 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, LYRICA (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 LYRICA-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 LYRICA, some patients reported

symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions (5.8)],

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 LYRICA. The highest reported accidental overdose of

LYRICA 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 LYRICA. 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 LYRICA.

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 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 is a white to off-white, crystalline solid with a pK of 4.2 and a pK of 10.6. It is freely

soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-

octanol/0.05M phosphate buffer) at pH 7.4 is – 1.35.

LYRICA (pregabalin) Capsules are administered orally and are supplied as imprinted hard-shell

capsules containing 75mg of pregabalin, along with lactose monohydrate, cornstarch, and talc as

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

capsule shells contain red iron oxide and the white capsule shells contain sodium lauryl sulfate and

colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be

present in the capsule shells. The imprinting ink contains shellac, black iron oxide, propylene glycol,

and potassium hydroxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

LYRICA (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 of action 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

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 LYRICA capsules under fasting conditions, peak plasma

concentrations occur within 1.5 hours. Pregabalin oral bioavailability is ≥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 67.0 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, (2.6)].

Pharmacokinetics in Special Populations

Race

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

pharmacokinetics of LYRICA 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 LYRICA 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 (2.6)].

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,

(2.6)].

Pediatric Pharmacokinetics

Pharmacokinetics of pregabalin have not been adequately studied in pediatric patients.

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 (3–4 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.

Human Data

In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility,

30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of

treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects

in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline

of more than 2%. Effects on other male reproductive parameters in humans have not been adequately

studied.

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) ≥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 LYRICA 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

≥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 LYRICA 25, 100, or 200 mg three times a day with placebo.

Treatment with LYRICA 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 LYRICA 100 mg three times a day with placebo. Treatment

with LYRICA 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 LYRICA 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

≥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 LYRICA 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 LYRICA 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 LYRICA 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 LYRICA 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 LYRICA 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 LYRICA 50 or 100 mg three times a day with placebo with

doses assigned regardless of creatinine clearance. Treatment with LYRICA 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 LYRICA 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 Adult Patients with Partial Onset Seizures

The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-

week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients. 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 LYRICA-treated patients,

80% completed the double-blind phase of the studies.

Table 8 shows median baseline seizure rates and median percent reduction in seizure frequency by

dose.

Table 8. Seizure Response in Controlled, Add-On Epilepsy Studies

Daily Dose of

Pregabalin

Dos ing

Regimen

N

Baseline Seizure

Frequency/mo

Median %

Change from

Bas eline

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 98

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

Lyrica 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 ≥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 add-on 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 LYRICA showed no clinically important differences

as a function of age, gender, or race.

14.4 Management of Fibromyalgia

The efficacy of LYRICA 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 LYRICA 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 LYRICA 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 8 and Table 9.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 8 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 8: Patients Achieving Various Levels of Improvement in Pain Intensity – Fibromyalgia Study F1

Table 9. Patient Global Response in Fibromyalgia Study F1

Patient Global Impression of Change

Treatment

Group

(mg/day)

% Any Improvement

95% CI

PGB = Pregabalin

Placebo

47.6

(40.0,55.2)

PGB 300

68.1

(60.9, 75.3)

PGB 450

77.8

(71.5, 84.0)

PGB 600

66.1

(59.1, 73.1)

Study F2: This randomized withdrawal study compared LYRICA 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 LYRICA during

the 6-week open-label phase. Of the patients entering the randomized treatment phase assigned to remain

on LYRICA, 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 LYRICA 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

LYRICA 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 .

Figure 9: 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 LYRICA 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 ≥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 (150–

600 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 LYRICA 150–600 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 10. Some patients experienced a decrease in pain as early as week 1, which persisted throughout

the study.

Figure 10: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 1

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."

Study SCI 2: This 16-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter,

flexible dose (150–600 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 LYRICA 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 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 2

16 HOW SUPPLIED/STORAGE AND HANDLING

75 mg capsules:

White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 75" on the body;

available in:

Bottles of 90: NDC 68258-7980-09

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room

Temperature).

See FDA-Approved Medication Guide

17 PATIENT COUNSELING INFORMATION

17.1 Medication Guide

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide

prior to taking LYRICA. Instruct patients to take LYRICA only as prescribed.

17.2 Angioedema

Advise patients that LYRICA 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 LYRICA and immediately seek medical care if they experience these symptoms

[see Warnings and Precautions (5.1)].

17.3 Hypersensitivity

Advise patients that LYRICA has been associated with hypersensitivity reactions such as wheezing,

dyspnea, rash, hives, and blisters. Instruct patients to discontinue LYRICA and immediately seek medical

care if they experience these symptoms [see Warnings and Precautions (5.2)].

17.4 Suicidal Thinking and Behavior

Patients, their caregivers, and families should be counseled that AEDs, including LYRICA, 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)].

17.5 Dizziness and Somnolence

Counsel patients that LYRICA 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 LYRICA to gauge whether or not it

affects their mental, visual, and/or motor performance adversely. [see Warnings and Precautions (5.6)].

17.6 Weight Gain and Edema

Counsel patients that LYRICA may cause edema and weight gain. Advise patients that concomitant

treatment with LYRICA 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)].

17.7 Abrupt or Rapid Discontinuation

Advise patients to take LYRICA as prescribed. Abrupt or rapid discontinuation may result in insomnia,

nausea, headache, anxiety, hyperhidrosis, or diarrhea. [see Warnings and Precautions (5.8)].

17.8 Ophthalmological Effects

Counsel patients that LYRICA may cause visual disturbances. Inform patients that if changes in vision

occur, they should notify their physician [see Warnings and Precautions (5.10)].

17.9 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 (5.11)].

17.10 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)].

17.11 Alcohol

Tell patients to avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the

impairment of motor skills and sedating effects of alcohol.

17.12 Use in Pregnancy

Instruct patients to notify their physician if they become pregnant or intend to become pregnant during

therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy

[see Use In Specific Populations (8.1) and (8.3)].

Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry

is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients

can call the toll free number 1-888-233-2334 [see Use In Specific Populations (8.1)].

17.13 Male Fertility

Inform men being treated with LYRICA 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)].

17.14 Dermatopathy

Instruct diabetic patients to pay particular attention to skin integrity while being treated with LYRICA.

Some animals treated with pregabalin developed skin ulcerations, although no increased incidence of

skin lesions associated with LYRICA was observed in clinical trials [see Nonclinical Toxicology (13.2)].

LAB-0294-23.0

MEDICATION GUIDE

LYRICA (LEER-i-kah)

(pregabalin)

Capsules and Oral Solution, CV

Read this Medication Guide before you start taking LYRICA 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 LYRICA, ask your

healthcare provider or pharmacist.

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

LYRICA may cause serious side effects including:

Serious, even life-threatening, allergic reactions

Suicidal thoughts or actions

Swelling of your hands, legs and feet

Dizziness and sleepiness

These serious side effects are described below:

1.

2.

Serious, even life-threatening, allergic reactions.

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

of a serious allergic reaction:

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

trouble breathing

rash, hives (raised bumps) or blisters

Like other antiepileptic drugs, LYRICA 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:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

3.

4.

What is LYRICA?

LYRICA is a prescription medicine used in adults, 18 years 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

partial seizures when taken together with other seizure medicines

fibromyalgia (pain all over your body)

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

LYRICA has not been studied in children under 18 years of age.

Who Should Not Take LYRICA?

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

See "What is the most important information I should know about LYRICA?" for the signs of an allergic

reaction.

See the end of this leaflet for a complete list of ingredients in LYRICA.

What should I tell my healthcare provider before taking LYRICA?

Before taking LYRICA, tell your healthcare provider about all your medical conditions, including if

you:

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

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

If you have suicidal thoughts or actions, do not stop LYRICA without first talking to a

healthcare provider.

Stopping LYRICA 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

LYRICA affects you. Ask your healthcare provider about when it will be okay to do these

activities.

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 LYRICA,

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 LYRICA.

are pregnant or plan to become pregnant. It is not known if LYRICA will harm your unborn

baby. You and your healthcare provider will have to decide if you should take LYRICA while you

are pregnant. If you become pregnant while taking LYRICA, 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.

are breastfeeding. It is not known if LYRICA passes into breast milk and if it can harm your

baby. You and your healthcare provider should discuss whether you should take LYRICA or

breast-feed, but you should not do both

Tell your healthcare provider about all the medicines you take including prescription and non-

prescription medicines, vitamins or herbal supplements. LYRICA 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 LYRICA. See "What is the most important information I should know about LYRICA?"

Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), 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 LYRICA. See "What are the possible side effects of LYRICA."

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 LYRICA.

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 LYRICA?

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

take and when to take it. Take LYRICA at the same times each day.

LYRICA 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 LYRICA without talking to your healthcare provider. If you stop taking LYRICA

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

may feel anxious. If you have epilepsy and you stop taking LYRICA suddenly, you may have

seizures more often. Talk with your healthcare provider about how to stop LYRICA 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 LYRICA, call your healthcare provider or poison control center, or go to the

nearest emergency room right away.

What should I avoid while taking LYRICA?

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

LYRICA affects you.

Do not drink alcohol while taking LYRICA. LYRICA and alcohol can affect each other and

increase side effects such as sleepiness and dizziness.

What are the possible side effects of LYRICA?

LYRICA may cause serious side effects, including:

See "What is the most important information I should know about LYRICA?"

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 LYRICA are:

dizziness

blurry vision

weight gain

sleepiness

trouble concentrating

swelling of hands and feet

dry mouth

LYRICA 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 LYRICA 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 LYRICA. 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 LYRICA?

Store LYRICA capsules and oral solution at room temperature, 59°F to 86°F (15°C to 30°C) in its

original package.

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

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

General information about LYRICA

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

use LYRICA for a condition for which it was not prescribed. Do not give LYRICA to other people,

even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about LYRICA. If you would like

more information, talk with your healthcare provider. You can ask your healthcare provider or

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

You can also visit the LYRICA website at www.LYRICA.com or call 1-866-459-7422 (1-866-

4LYRICA).

What are the ingredients In LYRICA?

Active ingredient: pregabalin

Inactive ingredients:

LYRICA capsules: lactose monohydrate, cornstarch, talc

Capsule shell: gelatin and titanium dioxide; Orange capsule shell: red iron oxide; White capsule shell:

sodium lauryl sulfate, colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that

may or may not be present in the capsule shells.

Imprinting ink: shellac, black iron oxide, propylene glycol, potassium hydroxide.

LYRICA oral solution: methylparaben, propylparaben, monobasic sodium phosphate anhydrous,

dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

LAB-0299-12.0

06/2013

PRINCIPAL DISPLAY PANEL

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 68258-7980-XX

NDC 68258-7980-09

LYRICA

pregabalin capsule

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 258 -

79 8 0 (NDC:0 0 71-10 14)

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

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

STARCH, CO RN (UNII: O8 232NY3SJ)

TALC (UNII: 7SEV7J4R1U)

GELATIN (UNII: 2G8 6 QN327L)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

SHELLAC (UNII: 46 N10 7B71O)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

PO TASSIUM HYDRO XIDE (UNII: WZH3C48 M4T)

Product Characteristics

Color

WHITE, ORANGE

S core

no sco re

S hap e

CAPSULE

S iz e

14mm

Flavor

Imprint Code

Pfiz e r;PGN;75

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 258 -79 8 0 -9

9 0 in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 21724

12/30 /20 0 4

Labeler -

Dispensing Solutions, Inc. (066070785)

Registrant -

PSS World Medical, Inc. (101822682)

Establishment

Dispensing Solutions, Inc.

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dispensing So lutio ns, Inc.

0 6 6 0 70 78 5

relabel(6 8 258 -79 8 0 ) , repack(6 8 258 -79 8 0 )

Revised: 7/2013

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