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Lyrica User Reviews >>

Lyrica
------

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Drug Descriptionfont sizeAAA

LYRICA
(pregabalin) Capsules CV

LYRICA
(pregabalin) Oral Solution CV

DRUG DESCRIPTION

Pregabalin is described chemically as
(S)-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C8H17NO2
and the molecular weight is 159.23. The chemical structure of
pregabalin is:

 LYRICA
(pregabalin) Structural Formula Illustration

Pregabalin is a white to off-white, crystalline solid with a pKa1 of
4.2 and a pKa2 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 25, 50, 75, 100, 150, 200,
225, and 300 mg 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.

LYRICA (pregabalin) oral solution, 20 mg/mL, is administered orally
and is supplied as a clear, colorless solution contained in a 16 fluid
ounce white HDPE bottle with a polyethylene-lined closure. The oral
solution contains 20 mg/mL of pregabalin, along with methylparaben,
propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium
phosphate anhydrous, sucralose, artificial strawberry #11545 and
purified water as inactive ingredients.

Last updated on RxList: 1/25/2010

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

DOSAGE AND ADMINISTRATION

Lyrica is given orally with or without food.

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

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.

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.

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.

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.

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.

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.

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

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:

CLCr =

140 -age (years)  x weight (kg)

(x 0.85 for female patients)

72x serum creatinine (mg/dL)

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

150

300

450

600

BID or TID

30–60

75

150

225

300

BID or TID

15–30

25–50

75

100–150

150

QD or BID

< 15

25

25–50

50–75

75

QD

Supplementary dosage following hemodialysis (mg)†

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

TID= Three divided doses; BID = Two divided doses; QD = Single daily
dose.
 Total daily dose (mg/day) should be divided as indicated by dose
regimen to provide mg/dose.
† Supplementary dose is a single additional dose.

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).

HOW SUPPLIED

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.

25 mg capsules:

White, hard-gelatin capsule printed with black ink "Pfizer" on the
cap, "PGN 25" on the body; available in:

Bottles of 90:

NDC 0071-1012-68

50 mg capsules:

White, hard-gelatin capsule printed with black ink "Pfizer" on the
cap, "PGN 50" and an ink band on the body, available in:

Bottles of 90:

NDC 0071-1013-68

Unit-Dose Blister Packages of 100:

NDC 0071-1013-41

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 0071-1014-68

Unit-Dose Blister Packages of 100:

NDC 0071-1014-41

100 mg capsules:

Orange, hard-gelatin capsule printed with black ink "Pfizer" on the
cap, "PGN 100" on the body, available in:

Bottles of 90:

NDC 0071-1015-68

Unit-Dose Blister Packages of 100:

NDC 0071-1015-41

150 mg capsules:

White hard gelatin capsule printed with black ink "Pfizer" on the cap,
"PGN 150" on the body, available in:

Bottles of 90:

NDC 0071-1016-68

Unit-Dose Blister Packages of 100:

NDC 0071-1016-41

200 mg capsules:

Light orange hard gelatin capsule printed with black ink "Pfizer" on
the cap, "PGN 200" on the body, available in:

Bottles of 90:

NDC 0071-1017-68

225 mg capsules:

White/light orange hard gelatin capsule printed with black ink
"Pfizer" on the cap, "PGN 225" on the body; available in:

Bottles of 90:

NDC 0071-1019-68

300 mg capsules:

White/orange hard gelatin capsule printed with black ink "Pfizer" on
the cap, "PGN 300" on the body, available in:

Bottles of 90:

NDC 0071-1018-68

20 mg/mL oral solution:

16 fluid ounce white high density polyethylene (HDPE) bottle with a
polyethylene-lined closure.

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). For the oral solution,
use within 45 days of first opening the bottle.

See FDA-Approved Medication Guide

Capsules manufactured by: Pfizer Pharmaceuticals LLC Vega Baja, PR
00694. Oral Solution manufactured by: Pfizer Inc Kalamazoo, MI 49001.
Dintributed by: Parke-Davis, Division of Pfizer Inc, NY, NY 10017.
Revised: Decmber 2009.

Last updated on RxList: 1/25/2010

SIDE EFFECTS

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 (3%). 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
N=77 %

150 mg/day
N=212 %

300 mg/day
N=321 %

600 mg/day
N=369 %

All PGB
N=979

Placebo
N=459 %

Body as a whole

Asthenia

4

2

4

7

5

2

Accidental injury

5

2

2

6

4

3

Back pain

0

2

1

2

2

0

Chest pain

4

1

1

2

2

1

Face edema

0

1

1

2

1

0

Digestive system

Dry mouth

3

2

5

7

5

1

Constipation

0

2

4

6

4

2

Flatulence

3

0

2

3

2

1

Metabolic and nutritional disorders

Peripheral edema

4

6

9

12

9

2

Weight gain

0

4

4

6

4

0

Edema

0

2

4

2

2

0

Hypoglycemia

1

3

2

1

2

1

Nervous system

Dizziness

8

9

23

29

21

5

Somnolence

4

6

13

16

12

3

Neuropathy

9

2

2

5

4

3

Ataxia

6

1

2

4

3

1

Vertigo

1

2

2

4

3

1

Confusion

0

1

2

3

2

1

Euphoria

0

0

3

2

2

0

Incoordination

1

0

2

2

2

0

Thinking abnormal†

1

0

1

3

2

0

Tremor

1

1

1

2

1

0

Abnormal gait

1

0

1

3

1

0

Amnesia

3

1

0

2

1

0

Nervousness

0

1

1

1

1

0

Respiratory system

Dyspnea

3

0

2

2

2

1

Special senses

Blurry vision‡

3

1

3

6

4

2

Abnormal vision

1

0

1

1

1

0

 PGB: pregabalin
† Thinking abnormal primarily consists of events related to difficulty
with concentration/attention but also includes events related to
cognition and language problems and slowed thinking.
‡ Investigator term; summary level term is amblyopia

Controlled Studies in Postherpetic Neuralgia

Adverse Reactions Leading to Discontinuation

In clinical trials in 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 events 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
N=84 %

150 mg/d
N=302 %

300 mg/d
N=312 %

600 mg/d
N=154 %

All PGB
N=852 %

Placebo
N=398 %

Body as a whole

Infection

14

8

6

3

7

4

Headache

5

9

5

8

7

5

Pain

5

4

5

5

5

4

Accidental injury

4

3

3

5

3

2

Flu syndrome

1

2

2

1

2

1

Face edema

0

2

1

3

2

1

Digestive system

Dry mouth

7

7

6

15

8

3

Constipation

4

5

5

5

5

2

Flatulence

2

1

2

3

2

1

Vomiting

1

1

3

3

2

1

Metabolic and nutritional disorders

Peripheral edema

0

8

16

16

12

4

Weight gain

1

2

5

7

4

0

Edema

0

1

2

6

2

1

Musculoskeletal system

Myasthenia

1

1

1

1

1

0

Nervous system

Dizziness

11

18

31

37

26

9

Somnolence

8

12

18

25

16

5

Ataxia

1

2

5

9

5

1

Abnormal gait

0

2

4

8

4

1

Confusion

1

2

3

7

3

0

Thinking abnormal†

0

2

1

6

2

2

Incoordination

2

2

1

3

2

0

Amnesia

0

1

1

4

2

0

Speech disorder

0

0

1

3

1

0

Respiratory system

Bronchitis

0

1

1

3

1

1

Special senses

Blurry vision‡

1

5

5

9

5

3

Diplopia

0

2

2

4

2

0

Abnormal vision

0

1

2

5

2

0

Eye Disorder

0

1

1

2

1

0

Urogenital System

Urinary Incontinence

0

1

1

2

1

0

 PGB: pregabalin
† Thinking abnormal primarily consists of events related to difficulty
with concentration/attention but also includes events related to
cognition and language problems and slowed thinking.
‡ Investigator term; summary level term is amblyopia

Controlled 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 addon 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 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 %

600mg/d
N = 395 %

All PGB
N = 670† %

Placebo
N = 294 %

Body as a Whole

Accidental Injury

7

11

10

9

5

Pain

3

2

5

4

3

Digestive System

Increased Appetite

2

3

6

5

1

Dry Mouth

1

2

6

4

1

Constipation

1

1

7

4

2

Metabolic and Nutritional Disorders

Weight Gain

5

7

16

12

1

Peripheral Edema

3

3

6

5

2

Nervous System

Dizziness

18

31

38

32

11

Somnolence

11

18

28

22

11

Ataxia

6

10

20

15

4

Tremor

3

7

11

8

4

Thinking Abnormal‡

4

8

9

8

2

Amnesia

3

2

6

5

2

Speech Disorder

1

2

7

5

1

Incoordination

1

3

6

4

1

Abnormal Gait

1

3

5

4

0

Twitching

0

4

5

4

1

Confusion

1

2

5

4

2

Myoclonus

1

0

4

2

0

Special Senses

Blurred Vision§

5

8

12

10

4

Diplopia

5

7

12

9

4

Abnormal Vision

3

1

5

4

1

 PGB: pregabalin
† Excludes patients who received the 50 mg dose in Study E1.
‡ Thinking abnormal primarily consists of events related to difficulty
with concentration/attention but also includes events related to
cognition and language problems and slowed thinking.
§ Investigator term; summary level term is amblyopia.

Controlled Studies with Fibromyalgia

Adverse Reactions Leading to Discontinuation

In clinical trials of patients with fibromyalgia, 19% of patients
treated with pregabalin (150–600 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
N=132 %

300 mg/d
N=502 %

450 mg/d
N=505 %

600 mg/d
N=378 %

All PGB
N=1517 %

Placebo
N=505 %

Ear and Labyrinth Disorders

Vertigo

2

2

2

1

2

0

Eye Disorders

Vision blurred

8

7

7

12

8

1

Gastrointestinal Disorders

Dry mouth

7

6

9

9

8

2

Constipation

4

4

7

10

7

2

Vomiting

2

3

3

2

3

2

Flatulence

1

1

2

2

2

1

Abdominal distension

2

2

2

2

2

1

General Disorders and Administrative Site Conditions

Fatigue

5

7

6

8

7

4

Edema peripheral

5

5

6

9

6

2

Chest pain

2

1

1

2

2

1

Feeling abnormal

1

3

2

2

2

0

Edema

1

2

1

2

2

1

Feeling drunk

1

2

1

2

2

0

Infections and Infestations

Sinusitis

4

5

7

5

5

4

Investigations

Weight increased

8

10

10

14

11

2

Metabolism and Nutrition Disorders

Increased appetite

4

3

5

7

5

1

Fluid retention

2

3

3

2

2

1

Musculoskeletal and Connective Tissue Disorders

Arthralgia

4

3

3

6

4

2

Muscle spasms

2

4

4

4

4

2

Back pain

2

3

4

3

3

3

Nervous System Disorders

Dizziness

23

31

43

45

38

9

Somnolence

13

18

22

22

20

4

Headache

11

12

14

10

12

12

Disturbance in attention

4

4

6

6

5

1

Balance disorder

2

3

6

9

5

0

Memory impairment

1

3

4

4

3

0

Coordination abnormal

2

1

2

2

2

1

Hypoaesthesia

2

2

3

2

2

1

Lethargy

2

2

1

2

2

0

Tremor

0

1

3

2

2

0

Psychiatric Disorders

Euphoric Mood

2

5

6

7

6

1

Confusional state

0

2

3

4

3

0

Anxiety

2

2

2

2

2

1

Disorientation

1

0

2

1

2

0

Depression

2

2

2

2

2

2

Respiratory, Thoracic and Mediastinal Disorders

Pharyngolaryngeal pain

2

1

3

3

2

2

PGB: pregabalin

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,
Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Stupor,
Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia,
Circumoral paresthesia, Dysarthria, Hallucinations, Hostility,
Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia,
Libido increased, Myoclonus, Neuralgia, Rare: Addiction, Cerebellar
syndrome, Cogwheel rigidity, Coma, Delirium, Delusions,

Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal
syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial
hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis,
Personality disorder, Psychotic depression, Schizophrenic reaction,
Sleep disorder, Torticollis, Trismus

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

Skin and Appendages – Frequent: Pruritus, Infrequent: Alopecia, Dry
skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash;
Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis,
Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular
rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson
syndrome, Subcutaneous nodule

Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media,
Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry
eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste
loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer,
Exophthalmos, Extraocular palsy, Iritis, Keratitis,
Keratoconjunctivitis, Miosis, Mydriasis, Night blindness,
Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis

Urogenital System – Frequent: Anorgasmia, Impotence, Urinary
frequency, Urinary incontinence; Infrequent: Abnormal ejaculation,
Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney
calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria,
Urinary retention, Urine abnormality; Rare: Acute kidney failure,
Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis,
Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis

Comparison of Gender and Race

The overall adverse event profile of pregabalin was similar between
women and men. There are insufficient data to support a statement
regarding the distribution of adverse experience reports by race.

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

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.

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.

Drug Abuse And Dependence

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).

Abuse

In a study of recreational users (N=15) of sedative/hypnotic drugs,
including alcohol, LYRICA (450mg, single dose) received subjective
ratings of "good drug effect," "high" and "liking" to a degree that
was similar to diazepam (30mg, 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%.

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, suggestive of
physical dependence.

Last updated on RxList: 1/25/2010

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

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.

Withdrawal of Antiepileptic Drugs (AEDs)

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.

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

Risk Difference: Additional Drug Patients with Events Per 1000
Patients

Epilepsy

1.0

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1.0

1.8

1.9

0.9

Total

2.4

4.3

1.8

1.9

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.

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.

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 INFORMATION.

In the LYRICA controlled trials, dizziness was experienced by 31% of
LYRICA-treated patients compared to 9% of placebo-treated patients;
somnolence was experienced by 22% of LYRICA-treated patients compared
to 7% 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.

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.

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 HbA1C).

Abrupt or Rapid Discontinuation

Following abrupt or rapid discontinuation of LYRICA, some patients
reported symptoms including insomnia, nausea, headache, and diarrhea.
Taper LYRICA gradually over a minimum of 1 week rather than
discontinuing the drug abruptly.

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. 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.

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
INFORMATION.

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.

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 × 103/µL, compared to 11 × 103/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 × 103/µL. A single LYRICA treated subject
developed severe thrombocytopenia with a platelet count less than 20 x
103/ µL. In randomized controlled trials, LYRICA was not associated
with an increase in bleeding-related adverse reactions.

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.

Patient Counseling Information

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.

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.

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.

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.

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.

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.

Abrupt or Rapid Discontinuation

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

Ophthalmological Effects

Counsel patients that LYRICA may cause visual disturbances. Inform
patients that if changes in vision occur, they should notify their
physician.

Creatine Kinase Elevations

Instruct patients to promptly report unexplained muscle pain,
tenderness, or weakness, particularly if accompanied by malaise or
fever.

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.

Alcohol

Tell patients to avoid consuming alcohol while taking LYRICA, as
LYRICA may potentiate the impairment of motor skills and sedating
effects of alcohol.

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.

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.

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.

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.

Nonclinical Toxicology

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.

Use In Specific Populations

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/.

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 (0–24) of 123 µg·hr/mL) at the maximum recommended
clinical dose of 600 mg/day.

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.

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.

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.

Last updated on RxList: 1/25/2010

OVERDOSE

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).

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.

Last updated on RxList: 1/25/2010

CLINICAL PHARMACOLOGY

Mechanism of Action

LYRICA (pregabalin) binds with high affinity to the alpha2-delta site
(an auxiliary subunit of voltage-gated calcium channels) in central
nervous system tissues. Although the mechanism of action of pregabalin
is unknown, results with genetically modified mice and with compounds
structurally related to pregabalin (such as gabapentin) suggest that
binding to the alpha2-delta subunit may be involved in pregabalin's
antinociceptive and antiseizure effects in animal models. In vitro,
pregabalin reduces the calcium-dependent release of several
neurotransmitters, possibly by modulation of calcium channel function.

While pregabalin is a structural derivative of the inhibitory
neurotransmitter gamma-aminobutyric acid (GABA), it does not bind
directly to GABAA, GABAB, or benzodiazepine receptors, does not
augment GABAA 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.

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 (Cmax) 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 Cmax of approximately 25% to 30% and an
increase in Tmax 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.

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.

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.

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 Diuretics

Glyburide, insulin, metformin 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

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.

Clinical Studies

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. For a range of
degrees of improvement in pain from baseline to study endpoint, Figure
1 shows the fraction of patients achieving that degree 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 Pain Relief – Study DPN
1

Patients Achieving Various Levels of Pain Relief – Study DPN 1 - Illustration

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 degrees of improvement in pain
from baseline to study endpoint, Figure 2 shows the fraction of
patients achieving that degree 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 Pain Relief – Study DPN
2

Patients Achieving Various Levels of Pain Relief – Study DPN 2 - Illustration

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 degrees of improvement in pain from baseline to study
endpoint, Figure 3 shows the fraction of patients achieving that
degree 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 Pain Relief – Study PHN
1

Patients Achieving Various Levels of Pain Relief – Study PHN 1 - Illustration

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 degrees of improvement in pain from baseline to study
endpoint, Figure 4 shows the fraction of patients achieving that
degree 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 Pain Relief – Study PHN
2

Patients Achieving Various Levels of Pain Relief – Study PHN 2 - Illustration

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
degrees of improvement in pain from baseline to study endpoint, Figure
5 shows the fraction of patients achieving that degree 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 Pain Relief – Study PHN
3

Patients Achieving Various Levels of Pain Relief – Study PHN 3 - Illustration

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 7 shows median baseline seizure rates and median percent
reduction in seizure frequency by dose.

Table 7: Seizure Response in Controlled, Add-On Epilepsy Studies

Daily Dose of Pregabalin

Dosing Regimen

N

Baseline Seizure Frequency/mo

Median % Change from Baseline

p-value, vs. placebo

Study E1

Placebo

BID

100

9.5

0

50 mg/day

BID

88

10.3

-9

0.4230

150 mg/day

BID

86

8.8

-35

0.0001

300 mg/day

BID

90

9.8

-37

0.0001

600 mg/day

BID

89

9.0

-51

0.0001

Study E2

Placebo

TID

96

9.3

1

150 mg/day

TID

99

11.5

-17

0.0007

600 mg/day

TID

92

12.3

-43

0.0001

Study E3

Placebo

BID/TID

98

11

-1

600 mg/day

BID

103

9.5

-36

0.0001

600 mg/day

TID

111

10

-48

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

Responder rate by add-on epilepsy study - Illustration

Figure 7. Seizure Reduction by Dose (All Partial Onset Seizures) for
Studies E1, E2, and E3

Seizure Reduction by Dose (All Partial Onset Seizures) for Studies E1, E2, and E3 - Illustration

Subset evaluations of the antiseizure efficacy of LYRICA showed no
clinically important differences as a function of age, gender, or
race.

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. 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 8.

For various degrees of improvement in pain from baseline to study
endpoint, Figure 8 shows the fraction of patients achieving that
degree 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 Pain Relief –
Fibromyalgia Study F1

Patients Achieving Various Levels of Pain Relief – Fibromyalgia Study F1 - Illustration

Table 8: Patient Global Response in Fibromyalgia Study F1

Patient Global Impression of Change

Treatment Group (mg/day)

% Any Improvement

95% CI

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)

PGB = Pregabalin

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 FIQ1,
and longer time to loss of overall assessment of patient status, as
measured by the PGIC2.

Figure 9: Time to Loss of Therapeutic Response, Fibromyalgia Study F2
(Kaplan-Meier Analysis)

Time to Loss of Therapeutic Response, Fibromyalgia Study F2 - Illustration

REFERENCES

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.

2. Time to PGIC lack of improvement was defined as time to PGIC
assessments indicating less improvement than “much improvement.”

Last updated on RxList: 1/25/2010

PATIENT INFORMATION

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?

1. LYRICA may cause 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

2. 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.

3. LYRICA may cause swelling of your hands, legs and feet. This
swelling can be a serious problem for people with heart problems.

4. LYRICA may cause 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)

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 or trouble sleeping. 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, 59oF
to 86°F (15oC to 30°C) in its original package.

LYRICA Oral Solution must be used within 45 days of first opening
the bottle.

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.

Last updated on RxList: 1/25/2010

Disclaimer

Consumer

IMPORTANT NOTE: This is a summary and does not contain all possible
information about this product. For complete information about this
product or your specific health needs, ask your health care
professional. Always seek the advice of your health care professional
if you have any questions about this product or your medical
condition. This information is not intended as individual medical
advice and does not substitute for the knowledge and judgment of your
health care professional. This information does not contain any
assurances that this product is safe, effective, or appropriate for
you.

PREGABALIN - ORAL

(pree-GAH-ba-lin)

COMMON BRAND NAME(S): Lyrica

USES: This medication is used to treat pain caused by nerve damage due
to diabetes and shingles (herpes zoster) infection. It is also used to
treat pain in people with fibromyalgia.

It is also used with other medications to treat certain types of
seizures (partial onset seizures).

HOW TO USE: Read the Patient Information Leaflet provided by your
pharmacist before you start using pregabalin and each time you get a
refill. If you have any questions regarding the information, consult
your doctor or pharmacist.

Take this medication by mouth, usually twice or three times a day, or
as directed by your doctor. You may take it with or without food. When
you start this medication, your dosage will probably need to be
increased slowly by your doctor to reduce side effects, especially
dizziness or drowsiness. Your dosage is based on your medical
condition and response to therapy.

Use this medication regularly in order to get the most benefit from
it. This drug works best when the amount of medicine in your body is
kept at a constant level. Therefore it is best to take pregabalin at
evenly spaced intervals throughout the day and night.

Do not stop taking this drug suddenly without your doctor's approval
since seizures may come back, or you may have a withdrawal reaction.

This medication may cause dependence, especially if it has been used
regularly for an extended period of time, or if it has been used in
high doses. In such cases, if you suddenly stop this drug, withdrawal
reactions may occur. Such reactions can include difficulty sleeping,
nausea, headache and diarrhea. Report to your doctor immediately any
such reactions. When stopping extended, regular treatment with this
drug, gradually reducing the dosage as directed will help prevent
withdrawal reactions. Consult your doctor or pharmacist for more
details.

Though it is very unlikely to occur, this medication can also result
in abnormal drug-seeking behavior (addiction/habit-forming). Do not
increase your dose, take it more frequently or use it for a longer
period of time than prescribed. Properly stop the medication when so
directed. This will lessen the chances of becoming addicted.

Inform your doctor if your condition persists or worsens.

Disclaimer

Consumer (continued)

SIDE EFFECTS: Drowsiness, dizziness, confusion, difficulty
concentrating, unsteadiness, fatigue, swollen arms/legs, increased
appetite, weight gain, nausea, dry mouth or constipation may occur. If
any of these effects persist or worsen, notify your doctor or
pharmacist promptly.

Remember that your doctor has prescribed this medication because he or
she has judged that the benefit to you is greater than the risk of
side effects. Many people using this medication do not have serious
side effects.

Tell your doctor immediately if any of these unlikely but serious side
effects occur: change in amount of urine, difficulty speaking, loss of
coordination, mental/mood changes, muscle pain/tenderness/weakness
(especially if you are tired or have a fever), stomach/abdominal pain,
uncontrolled movements (e.g., tremor, twitching), unusual tiredness,
vision changes.

This medication rarely may cause mood or behavior changes, such as
anxiety, agitation, hostility, pressured/rapid speech, or thoughts of
suicide. Tell your doctor immediately if you develop unusual (possibly
sudden) mood changes.

Tell your doctor immediately if any of these rare but very serious
side effects occur: unusual bleeding/bruising, slow or irregular
heartbeat.

A very serious allergic reaction to this drug is rare. However, seek
immediate medical attention if you notice any symptoms of a serious
allergic reaction, including: rash, itching/swelling (especially of
the face/tongue/lips/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice
other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The
following numbers do not provide medical advice, but in the US you may
report side effects to the Food and Drug Administration (FDA) at
1-800-FDA-1088. In Canada, you may call Health Canada at
1-866-234-2345.

PRECAUTIONS: Before taking pregabalin, tell your doctor or pharmacist
if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your
medical history, especially of: heart problems (e.g., heart failure),
kidney disease, a certain type of blood disorder (low platelet count),
history of an allergic reaction which included itching/swelling of the
face/lips/tongue/throat (angioedema).

This drug may make you dizzy or drowsy or cause blurred vision; use
caution engaging in activities requiring alertness such as driving or
using machinery. Avoid alcoholic beverages because they may increase
the risk of this drug's side effects.

Kidney function declines as you grow older. This medication is removed
by the kidneys. Caution is advised when using this drug in the elderly
because they may be more sensitive to its side effects, including
drowsiness, dizziness, unsteadiness, confusion.

This medication should be used only when clearly needed during
pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult
your doctor before breast-feeding.

Disclaimer

Consumer (continued)

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or
pharmacist) may already be aware of any possible drug interactions and
may be monitoring you for it. Do not start, stop or change the dosage
of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all
prescription and nonprescription/herbal products you may use.

Tell your doctor or pharmacist if you also take drugs that cause
drowsiness such as: certain antihistamines (e.g., diphenhydramine),
anti-anxiety drugs (e.g., diazepam), anti-seizure drugs (e.g.,
carbamazepine), medicine for sleep (e.g., sedatives), muscle
relaxants, narcotic pain relievers (e.g., codeine), psychiatric
medicines (e.g., phenothiazines such as chlorpromazine, or tricyclics
such as amitriptyline), tranquilizers.

Check the labels on all your medicines (e.g., cough-and-cold products)
because they may contain drowsiness-causing ingredients. Ask your
pharmacist about the safe use of those products.

This document does not contain all possible interactions. Therefore,
before using this product, tell your doctor or pharmacist of all the
products you use. Keep a list of all your medications with you, and
share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control
center or emergency room immediately. US residents can call the US
national poison hotline at 1-800-222-1222. Canadian residents should
call their local poison control center directly.

NOTES: Do not share this medication with others. It is against the
law. Laboratory tests may be done to measure kidney function.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it
is near the time of the next dose, skip the missed dose and resume
your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away
from light and moisture. Brief storage between 59-86 degrees F (15-30
degrees C) is permitted. Do not store in the bathroom. Keep all
medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain
unless instructed to do so. Properly discard this product when it is
expired or no longer needed. Consult your pharmacist or local waste
disposal company for more details about how to safely discard your
product.

MEDICAL ALERT: Your condition can cause complications in a medical
emergency. For enrollment information call MedicAlert at
1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank,
Inc.

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Lyrica User Reviews

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Patient Discussions.

Here is a collection of user reviews for the medication Lyrica sorted
by most helpful. Patient Discussions FAQs

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription
drugs to the FDA. Visit the FDA MedWatch website or call
1-800-FDA-1088.

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Warnings & Precautions

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