WWW - Fda.gov/medwatch 17

HIGHLIGHTS OF PRESCRIBING INFORMATION ------ DOSAGE FORMS AND STRENGTHS ------
• Capsules: 25mg, 50 mg, 75 mg, 100 mg, 150 mg, 200

These highlights do not include all the information
mg, 225 mg, and 300 mg. (3)
needed to use Lyrica safely and effectively. See full
------ CONTRAINDICATIONS ------
prescribing information for Lyrica.
• Known hypersensitivity to pregabalin or any of its
Lyrica (pregabalin) Capsules, CV components. (4)
Initial U.S. Approval: 2004 ----- WARNINGS AND PRECAUTIONS ---
------ INDICATIONS AND USAGE ------ • Angioedema (e.g. swelling of the throat, head and
LYRICA is indicated for: neck) can occur, and may be associated with life-
• Neuropathic pain associated with diabetic peripheral threatening respiratory compromise requiring
neuropathy (DPN) (1.1) emergency treatment. LYRICA should be discontinued
immediately in these cases. (5.1)
• Post herpetic neuralgia (PHN) (1.2)
• Hypersensitivity reactions (e.g. hives, dyspnea, and
• Adjunctive therapy for adult patients with partial wheezing) can occur. LYRICA should be discontinued
onset seizures (1.3) immediately in these patients. (5.2)
• Fibromyalgia (1.4) • Increased seizure frequency may occur in patients with
------ DOSAGE AND ADMINISTRATION ------ seizure disorders if LYRICA is rapidly discontinued.
DPN Pain (2.1): Withdraw LYRICA gradually over a minimum of 1
• Administer in 3 divided doses per day week. (5.3)
• Begin dosing at 150 mg/day • LYRICA may cause peripheral edema. Exercise caution
• May be increased to a maximum of 300 mg/day when co-administering LYRICA and thiazolidinedione
within 1 week. antidiabetic agents. (5.4)
PHN (2.2): • LYRICA may cause dizziness and somnolence and
• Administer in 2 or 3 divided doses per day impair patients’ ability to drive or operate
• Begin dosing at 150 mg/day machinery.(5.5)
• May be increased to 300 mg/day within 1 week
• Maximum dose of 600 mg/day. ------ ADVERSE REACTIONS ------
Adjunctive Therapy for Adult Patients with Partial Most common adverse reactions (≥ 5% and twice placebo)
Onset Seizures (2.3): are dizziness, somnolence, dry mouth, edema, blurred
• Administer in 2 or 3 divided doses per day
• Begin dosing at 150 mg/day vision, weight gain and thinking abnormal (primarily
• Maximum dose of 600 mg/day. difficulty with concentration/attention). (6.1)
FIBROMYALGIA (2.4):
To report SUSPECTED ADVERSE REACTIONS,
• Administer in 2 divided doses per day contact Pfizer at (800) 438-1985 or FDA at 1-800-
• Begin dosing at 150 mg/day FDA-1088 or www.fda.gov/medwatch
• May be increased to 300 mg/day within 1 week See 17 for PATIENT COUNSELING INFORMATION
• Maximum dose of 450 mg/day. and FDA approved patient labeling
Dose should be adjusted in patients with reduced renal Revised: 6/2007

function. (2.5)
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE 8.4 Pediatric Use
1.1 Management of neuropathic pain 8.5 Geriatric Use
associated with diabetic peripheral 9 DRUG ABUSE AND DEPENDENCE
neuropathy 9.1 Controlled Substance
1.2 Management of postherpetic neuralgia 9.2 Abuse
1.3 Adjunctive therapy for adult patients 9.3 Dependence
with partial onset seizures 10 OVERDOSAGE
1.4 Management of Fibromyalgia 11 DESCRIPTION
2 DOSAGE AND ADMINISTRATION 12 CLINICAL PHARMACOLOGY
2.1 Neuropathic pain associated with 12.1 Mechanism of Action
diabetic peripheral neuropathy 12.3 Pharmacokinetics
2.2 Postherpetic neuralgia 12.4 Pharmacokinetics in Special
2.3 Adjunctive therapy for adult patients Populations
with partial onset seizures 13 NONCLINICAL TOXICOLOGY
2.4 Fibromyalgia 13.1 Carcinogenesis, Mutagenesis,
2.5 Patients with Renal Impairment Impairment of Fertility
3 DOSAGE FORMS AND STRENGTHS 13.2 Animal Toxicology and/or
4 CONTRAINDICATIONS Pharmacology
5 WARNINGS AND PRECAUTIONS 14 CLINICAL STUDIES
5.1 Angioedema 14.1 Neuropathic pain associated with
5.2 Hypersensitivity diabetic peripheral neuropathy
5.3 Withdrawal of Antiepileptic Drugs 14.2 Postherpetic Neuralgia
(AEDs) 14.3 Adjunctive therapy for adult
5.4 Peripheral Edema patients with partial onset seizures
5.5 Dizziness and Somnolence 14.4 Fibromyalgia
5.6 Weight Gain 16 HOW SUPPLIED/STORAGE AND
5.7 Abrupt or Rapid Discontinuation HANDLING
5.8 Tumorigenic Potential 17 PATIENT COUNSELING INFORMATION
5.9 Ophthalmological Effects 17.1 Patient Package Insert
5.10 Creatine Kinase Elevations 17.2 Angioedema
5.11 Decreased Platelet Count 17.3 Hypersensitivity
5.12 PR Interval Prolongation 17.4 Dizziness and Somnolence
6 ADVERSE REACTIONS 17.5 Weight Gain and Edema
6.1 Clinical Trial Experience 17.6 Abrupt or Rapid Discontinuation
6.2 Postmarketing Experience 17.7 Ophthalmological Effects
7 DRUG INTERACTIONS 17.8 Creatine Kinase Elevations
8 USE IN SPECIFIC POPULATIONS 17.9 CNS Depressants
8.1 Pregnancy 17.10 Alcohol
8.2 Labor and Delivery 17.11 Use in Pregnancy
8.3 Nursing Mothers 17.12 Male Fertility
17.13 Dermatopathy
* Sections or subsections omitted from the full prescribing information are not listed
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE

LYRICA is indicated for:
1.1 Management of neuropathic pain associated with diabetic

peripheral neuropathy
1.2 Management of postherpetic neuralgia

1.3 Adjunctive therapy for adult patients with partial onset seizures
1.4 Management of fibromyalgia
2 DOSAGE AND ADMINISTRATION

Lyrica is given orally with or without food.
When discontinuing LYRICA, taper gradually over a minimum of 1 week.
2.1 Neuropathic pain associated with diabetic peripheral neuropathy

The maximum recommended dose of LYRICA is 100 mg three times a day
(300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Dosing
should begin at 50 mg three times a day (150 mg/day) and may be increased to
300 mg/day within 1 week based on efficacy and tolerability. Because LYRICA is
eliminated primarily by renal excretion, the dose should be adjusted for patients
with reduced renal function [see Dosage and Administration (2.5)].
Although LYRICA was also studied at 600 mg/day, there is no evidence that this
dose confers additional significant benefit and this dose was less well tolerated.
In view of the dose-dependent adverse reactions, treatment with doses above
300 mg/day is not recommended [see Adverse Reactions (6.1)].
2.2 Postherpetic neuralgia

The recommended dose of LYRICA is 75 to 150 mg two times a day, or 50 to
100 mg three times a day (150 to 300 mg/day) in patients with creatinine
clearance of at least 60 mL/min. Dosing should begin at 75 mg two times a day,
or 50 mg three times a day (150 mg/day) and may be increased to 300 mg/day
within 1 week based on efficacy and tolerability. Because LYRICA is eliminated
primarily by renal excretion, the dose should be adjusted for patients with
reduced renal function [see Dosage and Administration (2.5)].
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, dosing above 300 mg/day
should be reserved only for those patients who have on-going pain and are
tolerating 300 mg daily [see Adverse Reactions (6.1)].
2.3 Adjunctive therapy for adult patients with partial onset seizures
LYRICA at doses of 150 to 600 mg/day has been shown to be effective as
adjunctive therapy in the treatment of partial onset seizures in adults. The total
daily dose should be divided and given either two or three times daily. Both the
efficacy and adverse event profiles of LYRICA have been shown to be dose-
related. 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, the dose should be
adjusted for patients with reduced renal function [see Dosage and Administration
(2.5)].
The effect of dose escalation rate on the tolerability of LYRICA has not been
formally studied.
The efficacy of add-on LYRICA in patients taking gabapentin has not been
evaluated in controlled trials. Consequently, dosing recommendations for the use
of LYRICA with gabapentin cannot be offered.
2.4 Management of Fibromyalgia

The recommended dose of LYRICA for fibromyalgia is 300 to 450 mg/day.
Dosing should begin at 75 mg two times a day (150 mg/day) and may be
increased to 150 mg two times a day (300 mg/day) within 1 week based on
efficacy and tolerability. Patients who do not experience sufficient benefit with
300 mg/day may be further increased to 225 mg two times a day (450 mg/day).
Although LYRICA was also studied at 600 mg/day, there is no evidence that this
dose confers additional benefit and this dose was less well tolerated. In view of
the dose-dependent adverse reactions, treatment with doses above 450 mg/day
is not recommended [see Adverse Reactions (6.1)]. Because LYRICA is
eliminated primarily by renal excretion, the dose should be adjusted for patients
with reduced renal function (creatinine clearance less than 60 mL/min - see
Patients with Renal Impairment) [see Dosage and Administration (2.5)].
2.5 Patients with Renal Impairment
In view of dose-dependent adverse reactions and since LYRICA is eliminated

primarily by renal excretion, the dose should be adjusted in patients with
reduced renal function. Dosage adjustment in patients with renal impairment
should be based 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:
For patients undergoing hemodialysis, pregabalin daily dose should be adjusted

based on renal function. In addition to the daily dose adjustment, a
supplemental dose should be given immediately following every 4-hour
hemodialysis treatment (see Table 1).
Table 1. Pregabalin Dosage Adjustment Based on Renal Function
Creatinine Clearance Total Pregabalin Daily Dose
(CLcr) (mg/day)* Dose Regimen
(mL/min)
≥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.
3 DOSAGE FORMS AND STRENGTHS
Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg
[see Description (11) and How Supplied/Storage and Handling (16)].
4 CONTRAINDICATIONS
LYRICA is contraindicated in patients with known hypersensitivity to pregabalin

or any of its other components.
5 WARNINGS AND PRECAUTIONS
5.1 Angioedema
There have been postmarketing reports of angioedema in patients during initial

and chronic treatment with LYRICA. Specific symptoms included swelling of the
face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were
reports of life-threatening angioedema with respiratory compromise requiring
emergency treatment. LYRICA should be discontinued immediately in patients
with these symptoms.
Caution should be exercised when prescribing LYRICA to patients who have had
a previous episode of angioedema. In addition, patients who are taking other
drugs associated with angioedema (e.g., angiotensin converting enzyme
inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema.
5.2 Hypersensitivity
There have been postmarketing reports of hypersensitivity in patients shortly

after initiation of treatment with LYRICA. Adverse reactions included skin
redness, blisters, hives, rash, dyspnea, and wheezing. LYRICA should be
discontinued immediately in patients with these symptoms.
5.3 Withdrawal of Antiepileptic Drugs (AEDs)

As with all AEDs, LYRICA should be withdrawn gradually to minimize the
potential of increased seizure frequency in patients with seizure disorders. If
LYRICA is discontinued this should be done gradually over a minimum of 1 week.
5.4 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, care should be
taken 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, LYRICA should be
used with caution in these patients.
5.5 Dizziness and Somnolence

LYRICA may cause dizziness and somnolence. Patients should be informed that
LYRICA-related dizziness and somnolence may impair their ability to perform
tasks such as driving or operating machinery [see Patient Counseling Information
(17.4)].
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.
5.6 Weight Gain

LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of
up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9%
of LYRICA-treated patients and 2% of placebo-treated patients. Few patients
treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain.
LYRICA associated weight gain was related to dose and duration of exposure,
but did not appear to be associated with baseline BMI, gender, or age. Weight
gain was not limited to patients with edema [see Warnings and Precautions
(5.4)].
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).
5.7 Abrupt or Rapid Discontinuation

Following abrupt or rapid discontinuation of LYRICA, some patients reported
symptoms including insomnia, nausea, headache, and diarrhea. LYRICA should
be tapered gradually over a minimum of 1 week rather than discontinued
abruptly.
5.8 Tumorigenic Potential

In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an
unexpectedly high incidence of hemangiosarcoma was identified in two different
strains of mice [see Nonclinical Toxicology (13.1)]. The clinical significance of this
finding is unknown. Clinical experience during LYRICA’s premarketing
development provides no direct means to assess its potential for inducing tumors
in humans.
In clinical studies across various patient populations, comprising 6396 patient-
years of exposure in patients >12 years of age, new or worsening-preexisting
tumors were reported in 57 patients. Without knowledge of the background
incidence and recurrence in similar populations not treated with LYRICA, it is
impossible to know whether the incidence seen in these cohorts is or is not
affected by treatment.
5.9 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,
patients should be informed that if changes in vision occur, they should notify
their physician. If visual disturbance persists, further assessment should be
considered. More frequent assessment should be considered for patients who are
already routinely monitored for ocular conditions [see Patient Counseling
Information (17.7)].
5.10 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. Prescribers should instruct
patients to promptly report unexplained muscle pain, tenderness, or weakness,
particularly if these muscle symptoms are accompanied by malaise or fever.
LYRICA treatment should be discontinued if myopathy is diagnosed or suspected
or if markedly elevated creatine kinase levels occur.
5.11 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.
5.12 PR Interval Prolongation

LYRICA treatment was associated with PR interval prolongation. In analyses of
clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA
doses ≥300 mg/day. This mean change difference was not associated with an
increased risk of PR increase ≥25% from baseline, an increased percentage of
subjects with on-treatment PR >200 msec, or an increased risk of adverse
reactions of second or third degree AV block.
Subgroup analyses did not identify an increased risk of PR prolongation in
patients with baseline PR prolongation or in patients taking other PR prolonging
medications. However, these analyses cannot be considered definitive because of
the limited number of patients in these categories.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not reflect the
rates observed in practice.
In all controlled and uncontrolled trials across various patient populations during
the premarketing development of LYRICA, more than 10,000 patients have
received LYRICA. Approximately 5000 patients were treated for 6 months or
more, over 3100 patients were treated for 1 year or longer, and over 1400
patients were treated for at least 2 years.
Adverse Reactions Most Commonly Leading to Discontinuation in All
Premarketing Controlled Clinical Studies
In premarketing controlled trials of all populations combined, 14% of patients
treated with LYRICA and 7% of patients treated with placebo discontinued
prematurely due to adverse reactions. In the LYRICA treatment group, the
adverse reactions most frequently leading to discontinuation were dizziness (4%)
and somnolence (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 2 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 2 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 75 150 300 600
All PGB* Placebo
- Preferred mg/day mg/day mg/day mg/day
[N=979] [N=459]
term [N=77] [N=212] [N=321] [N=369]
% %
% % % %
Body as a
whole
Asthenia 4 2 4 7 5 2
Accidental
5 2 2 6 4 3
injury
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 4 6 9 12 9 2
edema
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 1 0 1 3 2 0
abnormal†
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
1 0 1 1 1 0
vision
* PGB: pregabalin
†
Thinking abnormal primarily consists of events related to difficulty with
concentration/attention but also includes events related to cognition and
language problems and slowed thinking.
‡
Investigator term; summary level term is amblyopia
Controlled Studies in Postherpetic Neuralgia

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).
Table 3 lists all adverse reactions, regardless of causality, occurring in ≥ 1% of
patients with neuropathic pain associated with postherpetic neuralgia in the
combined LYRICA group for which the incidence was greater in this combined
LYRICA group than in the placebo group. In addition, an event is included, even
if the incidence in the all LYRICA group is not greater than in the placebo group,
if the incidence of the event in the 600 mg/day group is more than twice that in
the placebo group. A majority of pregabalin-treated patients in clinical studies
had adverse reactions with a maximum intensity of "mild" or "moderate”.

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 75 150 300 600
All PGB* Placebo
- Preferred mg/d mg/d mg/d mg/d
[N=852] [N=398]
term [N=84] [N=302] [N=312] [N=154]
% %
% % % %
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 4 3 3 5 3
2
injury
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
Vomiting 1 1 3 3 2 1
Metabolic and nutritional disorders

Peripheral
0 8 16 16 12 4
edema
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
0 2 1 6 2 2
abnormal†
Incoordination 2 2 1 3 2 0
Amnesia 0 1 1 4 2 0
Speech
0 0 1 3 1 0
disorder
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
0 1 2 5 2 0
vision
Eye Disorder 0 1 1 2 1 0
Urogenital System
Urinary
0 1 1 2 1 0
Incontinence
* PGB: pregabalin
†
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
Approximately 15% of patients receiving LYRICA and 6% of patients receiving
placebo in add-on epilepsy trials discontinued prematurely due to adverse
reactions. In the LYRICA treatment group, the adverse reactions most frequently
leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence
(3%). In comparison, <1% of patients in the placebo group withdrew due to
each of these events. Other adverse reactions that led to discontinuation of at
least 1% of patients in the LYRICA group and at least twice as frequently
compared to the placebo group were asthenia, diplopia, blurred vision, thinking
abnormal, nausea, tremor, vertigo, headache, and confusion (which each led to
withdrawal in 2% or less of patients).
Table 4 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 4. 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
150 300 mg/d 600 All PGB* Placebo
Body System
mg/d mg/d
- Preferred Term [N = 185] [N = 90] [N = 395] [N = 670]† [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.
‡
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

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.
Table 5 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".

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 150 300 450 600
All PGB* Placebo
Class mg/d mg/d mg/d mg/d
[N=1517] [N=505]
- Preferred [N=132] [N=502] [N=505] [N=378]
% %
term % % % %
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
Vomiting 2 3 3 2 3 2
Abdominal 2 2 2 2 2 1
distension
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 4 3 5 7 5 1
appetite
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 4 4 6 6 5 1
attention
Balance disorder 2 3 6 9 5 0
Memory 1 3 4 4 3 0
impairment
Coordination 2 1 2 2 2 1
abnormal
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 2 1 3 3 2 2
pain
* 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, Suicide attempt, Rare: Anaphylactoid reaction,
Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis,
Shock, Suicide
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.
6.2 Post-marketing Experience

The following adverse reactions have been identified during postapproval use of
LYRICA. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Nervous System Disorders -– Headache
Gastrointestinal Disorders – Nausea, Diarrhea
7 DRUG INTERACTIONS
Since LYRICA is predominantly excreted unchanged in the urine, undergoes
negligible metabolism in humans (<2% of a dose recovered in urine as
metabolites), and does not bind to plasma proteins, its pharmacokinetics are
unlikely to be affected by other agents through metabolic interactions or protein
binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely
to be involved in significant pharmacokinetic drug interactions. Specifically, there
are no pharmacokinetic interactions between pregabalin and the following
antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin,
phenobarbital, and topiramate. Important pharmacokinetic interactions would
also not be expected to occur between LYRICA and commonly used antiepileptic
drugs [see Clinical Pharmacology (12)].
Pharmacodynamics
Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam,
or ethanol. Although no pharmacokinetic interactions were seen, additive effects
on cognitive and gross motor functioning were seen when LYRICA was co-
administered with these drugs. No clinically important effects on respiration were
seen.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C. Increased incidences of fetal structural abnormalities and
other manifestations of developmental toxicity, including lethality, growth
retardation, and nervous and reproductive system functional impairment, were
observed in the offspring of rats and rabbits given pregabalin during pregnancy,
at doses that produced plasma pregabalin exposures (AUC) ≥5 times human
exposure at the maximum recommended dose (MRD) of 600 mg/day.
When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally
throughout the period of organogenesis, incidences of specific skull alterations
attributed to abnormally advanced ossification (premature fusion of the jugal and
nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal
variations and retarded ossification were increased at all doses. Fetal body
weights were decreased at the highest dose. The low dose in this study was
associated with a plasma exposure (AUC) approximately 17 times human
exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal
developmental toxicity was not established.
When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally
throughout the period of organogenesis, decreased fetal body weight and
increased incidences of skeletal malformations, visceral variations, and retarded
ossification were observed at the highest dose. The no-effect dose for
developmental toxicity in rabbits (500 mg/kg) was associated with a plasma
exposure approximately 16 times human exposure at the MRD.
In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or
2500 mg/kg) throughout gestation and lactation, offspring growth was reduced
at ≥ 100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect
on offspring survival was pronounced at doses ≥1250 mg/kg, with 100%
mortality in high-dose litters. When offspring were tested as adults,
neurobehavioral abnormalities (decreased auditory startle responding) were
observed at ≥250 mg/kg and reproductive impairment (decreased fertility and
litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal
developmental toxicity in rats (50 mg/kg) produced a plasma exposure
approximately 2 times human exposure at the MRD.
There are no adequate and well-controlled studies in pregnant women. LYRICA
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
8.2 Labor and Delivery

The effects of LYRICA on labor and delivery in pregnant women are unknown. In
the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced
dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123
µg·hr/mL) at the maximum recommended clinical dose of 600 mg/day.
8.3 Nursing Mothers

It is not known if pregabalin is excreted in human milk; it is, however, present in
the milk of rats. Because many drugs are excreted in human milk, and because
of the potential for tumorigenicity shown for pregabalin in animal studies, a
decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use

The safety and efficacy of pregabalin in pediatric patients have not been
established.
In studies in which pregabalin (50 to 500 mg/kg) was orally administered to

young rats from early in the postnatal period (Postnatal Day 7) through sexual
maturity, neurobehavioral abnormalities (deficits in learning and memory, altered
locomotor activity, decreased auditory startle responding and habituation) and
reproductive impairment (delayed sexual maturation and decreased fertility in
males and females) were observed at doses ≥50 mg/kg. The neurobehavioral
changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and
water maze performance at ≥500 mg/kg in animals tested after cessation of
dosing and, thus, were considered to represent long-term effects. The low effect
dose for developmental neurotoxicity and reproductive impairment in juvenile
rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC)
approximately equal to human exposure at the maximum recommended dose of
600 mg/day. A no-effect dose was not established.
8.5 Geriatric Use

In controlled clinical studies of LYRICA in neuropathic pain associated with
diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and
73 patients were 75 years of age or older.
In controlled clinical studies of LYRICA in neuropathic pain associated with
postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379
patients were 75 years of age or older.
In controlled clinical studies of LYRICA in epilepsy, there were only 10 patients
65 to 74 years of age, and 2 patients who were 75 years of age or older.
No overall differences in safety and efficacy were observed between these
patients and younger patients.
In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were
65 years of age or older. Although the adverse reaction profile was similar
between the two age groups, the following neurological adverse reactions were
more frequent in patients 65 years of age or older: dizziness, vision blurred,
balance disorder, tremor, confusional state, coordination abnormal, and lethargy.
LYRICA is known to be substantially excreted by the kidney, and the risk of toxic
reactions to LYRICA may be greater in patients with impaired renal function.
Because LYRICA is eliminated primarily by renal excretion, the dose should be
adjusted for elderly patients with renal impairment [see Dosage and
Administration (2.5)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance

LYRICA is a Schedule V controlled substance.
LYRICA is not known to be active at receptor sites associated with drugs of
abuse. As with any CNS active drug, physicians should carefully evaluate patients
for history of drug abuse and observe them for signs of LYRICA misuse or abuse
(e.g., development of tolerance, dose escalation, drug-seeking behavior).
9.2 Abuse
In a study of recreational users (N=15) of sedative/hypnotic drugs, including
alcohol, LYRICA (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%.
9.3 Dependence
In clinical studies, following abrupt or rapid discontinuation of LYRICA, some
patients reported symptoms including insomnia, nausea, headache or diarrhea
[see Warnings and Precautions (5.7)], suggestive of physical dependence.
10 OVERDOSAGE
Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans
There is limited experience with overdose of LYRICA. The highest reported
accidental overdose of LYRICA during the clinical development program was
8000 mg, and there were no notable clinical consequences. In clinical studies,
some patients took as much as 2400 mg/day. The types of adverse reactions
experienced by patients exposed to higher doses (≥900 mg) were not clinically
different from those of patients administered recommended doses of LYRICA.
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; usual
precautions should be observed 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. A Certified Poison Control Center should be
contacted for up-to-date information on the management of overdose with
LYRICA.
Although hemodialysis has not been performed in the few known cases of
overdose, it may be indicated by the patient's clinical state or in patients with
significant renal impairment. Standard hemodialysis procedures result in
significant clearance of pregabalin (approximately 50% in 4 hours).
11 DESCRIPTION
Pregabalin is described chemically as (S)-3-(aminomethyl)-5-methylhexanoic
acid. The molecular formula is C8H17NO2 and the molecular weight is 159.23. The
chemical structure of pregabalin is:
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.
12 CLINICAL PHARMACOLOGY
12.1 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.
12.3 Pharmacokinetics
Pregabalin is well absorbed after oral administration, is eliminated largely by
renal excretion, and has an elimination half-life of about 6 hours.
Absorption and Distribution
Following oral administration of LYRICA capsules under fasting conditions, peak
plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is
≥90% and is independent of dose. Following single- (25 to 300 mg) and
multiple- dose (75 to 900 mg/day) administration, maximum plasma
concentrations (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, (2.5)].
12.4 Pharmacokinetics in Special Populations

Race
In population pharmacokinetic analyses of the clinical studies in various
populations, the pharmacokinetics of LYRICA were not significantly affected by
race (Caucasians, Blacks, and Hispanics).
Gender
Population pharmacokinetic analyses of the clinical studies showed that the
relationship between daily dose and LYRICA drug exposure is similar between
genders.
Renal Impairment and Hemodialysis
Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage
reduction in patients with renal dysfunction is necessary. Pregabalin is effectively
removed from plasma by hemodialysis. Following a 4-hour hemodialysis
treatment, plasma pregabalin concentrations are reduced by approximately 50%.
For patients on hemodialysis, dosing must be modified [see Dosage and
Administration (2.5)].
Elderly
Pregabalin oral clearance tended to decrease with increasing age. This decrease
in pregabalin oral clearance is consistent with age-related decreases in CLcr.
Reduction of pregabalin dose may be required in patients who have age-related
compromised renal function [see Dosage and Administration, (2.5)].
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
subjects had no effect on the rate and extent of oxycodone single-dose
pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no
Ethanol
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
Phenytoin, carbamazepine, valproic acid, and lamotrigine
Steady-state trough plasma concentrations of phenytoin, carbamazepine and
carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected
by concomitant pregabalin (200 mg three times a day) administration.
Population pharmacokinetic analyses in patients treated with pregabalin and
various concomitant medications suggest the following:
Therapeutic class Specific concomitant drug studied
Concomitant drug has no effect on the
pharmacokinetics of pregabalin
Hypoglycemics Glyburide, insulin, metformin
Diuretics Furosemide
Antiepileptic Drugs Tiagabine
Concomitant drug has no effect on the
pharmacokinetics of pregabalin and pregabalin has no
effect on the pharmacokinetics of concomitant drug
Antiepileptic Drugs Carbamazepine, lamotrigine,
phenobarbital, phenytoin, topiramate,
valproic acid
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
A dose-dependent increase in the incidence of malignant vascular tumors
(hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1)
given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma
pregabalin exposure (AUC) in mice receiving the lowest dose that increased
hemangiosarcomas was approximately equal to the human exposure at the
maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for
induction of hemangiosarcomas in mice was not established. No evidence of
carcinogenicity was seen in two studies in Wistar rats following dietary
administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in
males and 100, 300, or 900 mg/kg in females) that were associated with plasma
exposures in males and females up to approximately 14 and 24 times,
respectively, human exposure at the MRD.
Mutagenesis
Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not
clastogenic in mammalian systems in vitro and in vivo, and did not induce
unscheduled DNA synthesis in mouse or rat hepatocytes.
Impairment of Fertility
In fertility studies in which male rats were orally administered pregabalin (50 to
2500 mg/kg) prior to and during mating with untreated females, a number of
adverse reproductive and developmental effects were observed. These included
decreased sperm counts and sperm motility, increased sperm abnormalities,
reduced fertility, increased preimplantation embryo loss, decreased litter size,
decreased fetal body weights, and an increased incidence of fetal abnormalities.
Effects on sperm and fertility parameters were reversible in studies of this
duration (3–4 months). The no-effect dose for male reproductive toxicity in these
studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC)
approximately 3 times human exposure at the maximum recommended dose
(MRD) of 600 mg/day.
In addition, adverse reactions on reproductive organ (testes, epididymides)
histopathology were observed in male rats exposed to pregabalin (500 to
1250 mg/kg) in general toxicology studies of four weeks or greater duration. The
no-effect dose for male reproductive organ histopathology in rats (250 mg/kg)
was associated with a plasma exposure approximately 8 times human exposure
at the MRD.
In a fertility study in which female rats were given pregabalin (500, 1250, or
2500 mg/kg) orally prior to and during mating and early gestation, disrupted
estrous cyclicity and an increased number of days to mating were seen at all
doses, and embryolethality occurred at the highest dose. The low dose in this
study produced a plasma exposure approximately 9 times that in humans
receiving the MRD. A no-effect dose for female reproductive toxicity in rats was
not established.
Human Data
In a double-blind, placebo-controlled clinical trial to assess the effect of
pregabalin on sperm motility, 30 healthy male subjects were exposed to
pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete
sperm cycle), the difference between placebo- and pregabalin-treated subjects in
mean percent sperm with normal motility was <4% and neither group had a
mean change from baseline of more than 2%. Effects on other male reproductive
parameters in humans have not been adequately studied.
13.2 Animal Toxicology and/or Pharmacology

Dermatopathy
Skin lesions ranging from erythema to necrosis were seen in repeated-dose
toxicology studies in both rats and monkeys. The etiology of these skin lesions is
unknown. At the maximum recommended human dose (MRD) of 600 mg/day,
there is a 2-fold safety margin for the dermatological lesions. The more severe
dermatopathies involving necrosis were associated with pregabalin exposures (as
expressed by plasma AUCs) of approximately 3 to 8 times those achieved in
humans given the MRD. No increase in incidence of skin lesions was observed in
clinical studies.
Ocular Lesions
Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor
cells] and/or corneal inflammation/mineralization) were observed in two lifetime
carcinogenicity studies in Wistar rats. These findings were observed at plasma
pregabalin exposures (AUC) ≥2 times those achieved in humans given the
maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions
was not established. Similar lesions were not observed in lifetime carcinogenicity
studies in two strains of mice or in monkeys treated for 1 year.
14 CLINICAL STUDIES
14.1 Neuropathic pain associated with diabetic peripheral neuropathy

The efficacy of the maximum recommended dose of LYRICA for the management
of neuropathic pain associated with diabetic peripheral neuropathy was
established in three double-blind, placebo-controlled, multicenter studies with
three times a day dosing, two of which studied the maximum recommended
dose. Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a
diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to
5 years. A total of 89% of patients completed Studies DPN 1 and DPN 2. The
patients had a minimum mean baseline pain score of ≥4 on an 11-point
numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).
The baseline mean pain scores across the two studies ranged from 6.1 to 6.7.
Patients were permitted up to 4 grams of acetaminophen per day as needed for
pain, in addition to pregabalin. Patients recorded their pain daily in a diary.
Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three
times a day with placebo. Treatment with LYRICA 100 and 200 mg three times a
day statistically significantly improved the endpoint mean pain score and
increased the proportion of patients with at least a 50% reduction in pain score
from baseline. There was no evidence of a greater effect on pain scores of the
200 mg three times a day dose than the 100 mg three times a day dose, but
there was evidence of dose dependent adverse reactions [see Adverse Reactions
(6.1)]. For a range of 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
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
14.2 Postherpetic Neuralgia

The efficacy of LYRICA for the management of postherpetic neuralgia was
established in three double-blind, placebo-controlled, multicenter studies. These
studies enrolled patients with neuralgia persisting for at least 3 months following
healing of herpes zoster rash and a minimum baseline score of ≥4 on an 11-point
numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).
Seventy-three percent of patients completed the studies. The baseline mean pain
scores across the 3 studies ranged from 6 to 7. Patients were permitted up to 4
grams of acetaminophen per day as needed for pain, in addition to pregabalin.
Patients recorded their pain daily in a diary.
Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice
daily with placebo. Patients with creatinine clearance (CLcr) between 30 to 60
mL/min were randomized to 75 mg, 150 mg, or placebo twice daily. Patients with
creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150
mg, 300 mg or placebo twice daily. In patients with creatinine clearance greater
than 60 mL/min treatment with all doses of LYRICA statistically significantly
improved the endpoint mean pain score and increased the proportion of patients
with at least a 50% reduction in pain score from baseline. Despite differences in
dosing based on renal function, patients with creatinine clearance between 30 to
60 mL/min tolerated LYRICA less well than patients with creatinine clearance
greater than 60 mL/min as evidenced by higher rates of discontinuation due to
adverse reactions. For various 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
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.
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.
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.
14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures
The efficacy of LYRICA as adjunctive therapy in partial onset seizures was
established in three 12-week, randomized, double-blind, placebo-controlled,
multicenter studies in adult patients. Patients were enrolled who had partial
onset seizures with or without secondary generalization and were not adequately
controlled with 1 to 3 concomitant antiepileptic drugs (AEDs). Patients taking
gabapentin were required to discontinue gabapentin treatment 1 week prior to
entering baseline. During an 8-week baseline period, patients had to experience
at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks.
The mean duration of epilepsy was 25 years in these 3 studies and the mean and
median baseline seizure frequencies were 22.5 and 10 seizures per month,
respectively. Approximately half of the patients were taking 2 concurrent AEDs at
baseline. Among the LYRICA-treated patients, 80% completed the double-blind
phase of the studies.
Table 6 shows median baseline seizure rates and median percent reduction in
seizure frequency by dose.
Table 6: Seizure Response in Controlled, Add-On Epilepsy

Studies
Daily Dose Dosing N Baseline Seizure Median % p-value,
of Regimen Frequency/mo Change from vs.
Pregabalin Baseline 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
Figure 7. Seizure Reduction by Dose (All Partial Onset Seizures) for Studies E1,
E2, and E3
Subset evaluations of the antiseizure efficacy of LYRICA showed no clinically

important differences as a function of age, gender, or race.
14.4 Management of Fibromyalgia
The efficacy of LYRICA for management of fibromyalgia was established in one
14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-
month, randomized withdrawal study (F2). Studies F1 and F2 enrolled patients
with a diagnosis of fibromyalgia using the American College of Rheumatology
(ACR) criteria (history of widespread pain for 3 months, and pain present at 11
or more of the 18 specific tender point sites). The studies showed a reduction in
pain by visual analog scale. In addition, improvement was demonstrated based
on a patient global assessment (PGIC), and on the Fibromyalgia Impact
Questionnaire (FIQ).
Study F1: This 14-week study compared LYRICA total daily doses of 300 mg, 450
mg and 600 mg with placebo. Patients were enrolled with a minimum mean
baseline pain score of greater than or equal to 4 on an 11-point numeric pain
rating scale and a score of greater than or equal to 40 mm on the 100 mm pain
visual analog scale (VAS). The baseline mean pain score in this trial was 6.7.
Responders to placebo in an initial one-week run-in phase were not randomized
into subsequent phases of the study. A total of 64% of patients randomized to
LYRICA completed the study. There was no evidence of a greater effect on pain
scores of the 600 mg daily dose than the 450 mg daily dose, but there was
evidence of dose-dependent adverse reactions [see Adverse Reactions (6.1)].
Some patients experienced a decrease in pain as early as Week 1, which
persisted throughout the study. The results are summarized in Figure 8 and
Table 7.
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
Pregabalin 600mg daily dose

100
90 Placebo
80
Percent of Patients Improved
70
60
50
40
30
20
10
0
>0 ≥10 ≥20 ≥30 ≥40 ≥50 ≥60 ≥70 ≥80 ≥90 100
Percent Improvement in Pain from Baseline
Table 7: Patient Global Response in

Fibromyalgia Study F1
Patient Global Impression of Change

Treatmen
t Group % Any Improvement
(mg/day) 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.
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.”
Figure 9: Time to Loss of Therapeutic Response, Fibromyalgia Study F2

(Kaplan-Meier Analysis)
100%
Pregabalin
Placebo
90%
Estimated % Subjects without LTR
80%
70%
60%
50%
40%
30%
20%
10%
0%
0 20 40 60 80 100 120 140 160 180
Days
16 HOW SUPPLIED/STORAGE AND HANDLING
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
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
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
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
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see
USP Controlled Room Temperature).
See FDA-Approved Patient Labeling
17 PATIENT COUNSELING INFORMATION
17.1 Patient Package Insert

Patients should be informed of the availability of a patient information leaflet,
and they should be instructed to read the leaflet prior to taking LYRICA.
17.2 Angioedema
Patients should be advised 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. Patients should be instructed to
discontinue LYRICA and immediately seek medical care if they experience these
symptoms [see Warnings and Precautions (5.1)].
17.3 Hypersensitivity
Patients should be advised that LYRICA has been associated with hypersensitivity
reactions such as wheezing, dyspnea, rash, hives, and blisters. Patients should
be instructed to discontinue LYRICA and immediately seek medical care if they
experience these symptoms [see Warnings and Precautions (5.2)]
17.4 Dizziness and Somnolence

Patients should be counseled that LYRICA may cause dizziness, somnolence,
blurred vision and other CNS signs and symptoms. Accordingly, they should be
advised not to drive, operate complex machinery, or engage in other hazardous
activities until they have gained sufficient experience on LYRICA to gauge
whether or not it affects their mental, visual, and/or motor performance
adversely. [see Warnings and Precautions (5.5)].
17.5 Weight Gain and Edema

Patients should be counseled that LYRICA may cause edema and weight gain.
Patients should be advised that concomitant treatment with LYRICA and a
thiazolidinedione antidiabetic agent may lead to an additive effect on edema and
weight gain. For patients with preexisting cardiac conditions, this may increase
the risk of heart failure. [see Warnings and Precautions (5.4 and 5.6)].
17.6 Abrupt or Rapid Discontinuation

Patients should be advised to take LYRICA as prescribed. Abrupt or rapid
discontinuation may result in insomnia, nausea, headache, or diarrhea. [see
Warnings and Precautions (5.7)].
17.7 Ophthalmological Effects

Patients should be counseled that LYRICA may cause visual disturbances.
Patients should be informed that if changes in vision occur, they should notify
their physician [see Warnings and Precautions (5.9)].
17.8 Creatine Kinase Elevations

Patients should be instructed to promptly report unexplained muscle pain,
tenderness, or weakness, particularly if accompanied by malaise or fever. [see
Warnings and Precautions (5.10)].
17.9 CNS Depressants

Patients who require concomitant treatment with central nervous system
depressants such as opiates or benzodiazepines should be informed that they
may experience additive CNS side effects, such as somnolence.
17.10 Alcohol
Patients should be told to avoid consuming alcohol while taking LYRICA, as
LYRICA may potentiate the impairment of motor skills and sedating effects of
alcohol.
17.11 Use in Pregnancy

Patients should be instructed to notify their physician if they become pregnant or
intend to become pregnant during therapy, and to notify their physician if they
are breast feeding or intend to breast feed during therapy [see Use In Specific
Populations (8.1) and (8.3)].
17.12 Male Fertility

Men being treated with LYRICA who plan to father a child should be informed of
the potential risk of male-mediated teratogenicity. In preclinical studies in rats,
pregabalin was associated with an increased risk of male-mediated
teratogenicity. The clinical significance of this finding is uncertain [see Nonclinical
Toxicology (13.1)].
17.13 Dermatopathy
Diabetic patients should be instructed to pay particular attention to skin integrity
while being treated with LYRICA. Some animals treated with pregabalin
developed skin ulcerations, although no increased incidence of skin lesions
associated with LYRICA was observed in clinical trials [see Nonclinical Toxicology
(13.2)].
Manufactured by:
Pfizer Pharmaceuticals LLC
Vega Baja, PR 00694
LAB-0294-14.0

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HIGHLIGHTS OF PRESCRIBING INFORMATION ------ DOSAGE FORMS AND STRENGTHS ------

• Capsules: 25mg, 50 mg, 75 mg, 100 mg, 150 mg, 200

Dose should be adjusted in patients with reduced renal Revised: 6/2007

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Management of neuropathic pain associated with diabetic

1.2 Management of postherpetic neuralgia

1.4 Management of fibromyalgia

2 DOSAGE AND ADMINISTRATION

2.1 Neuropathic pain associated with diabetic peripheral neuropathy

2.2 Postherpetic neuralgia

2.4 Management of Fibromyalgia

2.5 Patients with Renal Impairment

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

For patients undergoing hemodialysis, pregabalin daily dose should be adjusted

3 DOSAGE FORMS AND STRENGTHS

LYRICA is contraindicated in patients with known hypersensitivity to pregabalin

5 WARNINGS AND PRECAUTIONS

There have been postmarketing reports of angioedema in patients during initial

There have been postmarketing reports of hypersensitivity in patients shortly

5.3 Withdrawal of Antiepileptic Drugs (AEDs)

5.4 Peripheral Edema

5.5 Dizziness and Somnolence

5.6 Weight Gain

5.7 Abrupt or Rapid Discontinuation

5.8 Tumorigenic Potential

5.9 Ophthalmological Effects

5.10 Creatine Kinase Elevations

5.11 Decreased Platelet Count

5.12 PR Interval Prolongation

6.1 Clinical Trials Experience

Table 2 Treatment-emergent adverse reaction incidence in

Metabolic and nutritional disorders

Controlled Studies in Postherpetic Neuralgia

Table 3 Treatment-emergent adverse reaction incidence in

Metabolic and nutritional disorders

Metabolic and Nutritional Disorders

Controlled Studies with Fibromyalgia

Table 5 Treatment-emergent adverse reaction incidence in

Other Adverse Reactions Observed During the Clinical Studies of LYRICA

6.2 Post-marketing Experience

8 USE IN SPECIFIC POPULATIONS

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

In studies in which pregabalin (50 to 500 mg/kg) was orally administered to

8.5 Geriatric Use

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

12.1 Mechanism of Action

12.4 Pharmacokinetics in Special Populations

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14.1 Neuropathic pain associated with diabetic peripheral neuropathy

14.2 Postherpetic Neuralgia

Table 6: Seizure Response in Controlled, Add-On Epilepsy

Subset evaluations of the antiseizure efficacy of LYRICA showed no clinically

Pregabalin 600mg daily dose

Percent Improvement in Pain from Baseline