INDICATIONS & USAGE SECTION

• LYRICA is indicated for:

  • Management of neuropathic pain associated with diabetic peripheral neuropathy
  • Management of postherpetic neuralgia
  • Adjunctive therapy for adult patients with partial onset seizures
  • Management of fibromyalgia
  • Management of neuropathic pain associated with spinal cord injury

DOSAGE & ADMINISTRATION SECTION

• LYRICA is given orally with or without food.

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

  2.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

  The maximum recommended dose of LYRICA is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6)].

  Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional significant benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 300 mg/day is not recommended [see Adverse Reactions (6.1)].

  2.2 Postherpetic Neuralgia

  The recommended dose of LYRICA is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 75 mg two times a day, or 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6)].

  Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 300 mg/day, and who are able to tolerate LYRICA, may be treated with up to 300 mg two times a day, or 200 mg three times a day (600 mg/day). In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, reserve dosing above 300 mg/day for those patients who have on-going pain and are tolerating 300 mg daily [see Adverse Reactions (6.1)].

  2.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures

  LYRICA at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. Both the efficacy and adverse event profiles of LYRICA have been shown to be dose-related. Administer the total daily dose in two or three divided doses. In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day.

  Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6)].

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

  The efficacy of add-on LYRICA in patients taking gabapentin has not been evaluated in controlled trials. Consequently, dosing recommendations for the use of LYRICA with gabapentin cannot be offered.

  2.4 Management of Fibromyalgia

  The recommended dose of LYRICA for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day). Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended [see Adverse Reactions (6.1)]. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6)].

  2.5 Neuropathic Pain Associated with Spinal Cord Injury

  The recommended dose range of LYRICA for the treatment of neuropathic pain associated with spinal cord injury is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient pain relief after 2 to 3 weeks of treatment with 150 mg two times a day and who tolerate LYRICA may be treated with up to 300 mg two times a day [see Clinical Studies (14.5)]. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.6)].

  2.6 Patients with Renal Impairment

  In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient's CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:

  Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose.

  (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)

  For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).

  Table 1. Pregabalin Dosage Adjustment Based on Renal Function

  Creatinine Clearance (CLcr) (mL/min)	Total Pregabalin Daily Dose (mg/day) *	Dose Regimen
  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.
  ≥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

  2.7 Oral Solution Concentration and Dispensing

  The oral solution is 20 mg pregabalin per milliliter (mL) and prescriptions should be written in milligrams (mg). The pharmacist will calculate the applicable dose in mL for dispensing (e.g., 150 mg equals 7.5 mL oral solution).

DOSAGE FORMS & STRENGTHS SECTION

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

Oral Solution: 20 mg/mL

CONTRAINDICATIONS SECTION

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.

WARNINGS AND PRECAUTIONS SECTION

• 5.1 Angioedema

  There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms.

  Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema.

  5.2 Hypersensitivity

  There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms.

  5.3 Withdrawal of Antiepileptic Drugs (AEDs)

  As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week.

  5.4 Suicidal Behavior and Ideation

  Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

  Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

  The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

  The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.

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

  Table 2. Risk by indication for antiepileptic drugs in the pooled analysis

  Indication	Placebo Patients with Events Per 1000 Patients	Drug Patients with Events Per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	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.

  5.5 Peripheral Edema

  LYRICA treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.

  In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema.

  Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs.

  As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering LYRICA and these agents.

  Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients.

  5.6 Dizziness and Somnolence

  LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery [see Patient Counseling Information (17.5)].

  In the LYRICA controlled trials, dizziness was experienced by 30% of LYRICA-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of LYRICA-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients [see Drug Interactions (7)].

  5.7 Weight Gain

  LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions (5.5)].

  Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown.

  Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg.

  While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C).

  5.8 Abrupt or Rapid Discontinuation

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

  5.9 Tumorigenic Potential

  In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology (13.1)]. The clinical significance of this finding is unknown. Clinical experience during LYRICA's premarketing development provides no direct means to assess its potential for inducing tumors in humans.

  In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment.

  5.10 Ophthalmological Effects

  In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision).

  Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients.

  Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions [see Patient Counseling Information (17.8)].

  5.11 Creatine Kinase Elevations

  LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.

  5.12 Decreased Platelet Count

  LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 × 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 × 103/ µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions.

  5.13 PR Interval Prolongation

  LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block.

  Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.

ADVERSE REACTIONS SECTION

• 6.1 Clinical Trials Experience

  Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

  In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years.

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

  In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).

  Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies

  In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and "thinking abnormal" (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo).

  Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

  Adverse Reactions Leading to Discontinuation

  In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients.

  Most Common Adverse Reactions

  Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate".

  Table 3. Treatment-emergent adverse reaction incidence in controlled trials in neuropathic pain associated with diabetic peripheral neuropathy (events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group)

  Body system Preferred term	75 mg/day	150 mg/day	300 mg/day	600 mg/day	All PGB *	Placebo
  	[N=77] %	[N=212] %	[N=321] %	[N=369] %	[N=979] %	[N=459] %
  *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
  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

  Controlled Studies in Postherpetic Neuralgia

  Adverse Reactions Leading to Discontinuation

  In clinical trials in patients with postherpetic neuralgia, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (4%) and somnolence (3%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring in greater frequency in the LYRICA group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia, ataxia, and abnormal gait (1% each).

  Most Common Adverse Reactions

  Table 4 lists all adverse reactions, regardless of causality, occurring in ≥ 1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. In addition, an event is included, even if the incidence in the all LYRICA group is not greater than in the placebo group, if the incidence of the event in the 600 mg/day group is more than twice that in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate". Overall, 12.4% of all pregabalin-treated patients and 9.0% of all placebo-treated patients had at least one severe event while 8% of pregabalin-treated patients and 4.3% of placebo-treated patients had at least one severe treatment-related adverse event.

  Table 4. Treatment-emergent adverse reaction incidence in controlled trials in neuropathic pain associated with postherpetic neuralgia (events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group)

  Body system Preferred term	75 mg/d	150 mg/d	300 mg/d	600 mg/d	All PGB *	Placebo
  	[N=84] %	[N=302] %	[N=312] %	[N=154] %	[N=852] %	[N=398] %
  *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
  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

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

  Adverse Reactions Leading to Discontinuation

  Approximately 15% of patients receiving LYRICA and 6% of patients receiving placebo in add-on epilepsy trials discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, <1% of patients in the placebo group withdrew due to each of these events. Other adverse reactions that led to discontinuation of at least 1% of patients in the LYRICA group and at least twice as frequently compared to the placebo group were asthenia, diplopia, blurred vision, thinking abnormal, nausea, tremor, vertigo, headache, and confusion (which each led to withdrawal in 2% or less of patients).

  Most Common Adverse Reactions

  Table 5 lists all dose-related adverse reactions occurring in at least 2% of all LYRICA-treated patients. Dose-relatedness was defined as the incidence of the adverse event in the 600 mg/day group was at least 2% greater than the rate in both the placebo and 150 mg/day groups. In these studies, 758 patients received LYRICA and 294 patients received placebo for up to 12 weeks. Because patients were also treated with 1 to 3 other AEDs, it is not possible to determine whether the following adverse reactions can be ascribed to LYRICA alone, or the combination of LYRICA and other AEDs. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate".

  Table 5. Dose-related treatment-emergent adverse reaction incidence in controlled trials in adjunctive therapy for adult patients with partial onset seizures (events in at least 2% of all LYRICA-treated patients and the adverse reaction in the 600 mg/day group was ≥2% the rate in both the placebo and 150 mg/day groups)

  Body System Preferred Term	150 mg/d [N = 185] %	300 mg/d [N = 90] %	600 mg/d [N = 395] %	All PGB * [N = 670] † %	Placebo [N = 294] %
  *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.
  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

  Controlled Studies with Fibromyalgia

  Adverse Reactions Leading to Discontinuation

  In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150–600 mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (6%) and somnolence (3%). In comparison, <1% of placebo-treated patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue, headache, balance disorder, and weight increased. Each of these adverse reactions led to withdrawal in approximately 1% of patients.

  Most Common Adverse Reactions

  Table 6 lists all adverse reactions, regardless of causality, occurring in ≥2% of patients with fibromyalgia in the 'all pregabalin' treatment group for which the incidence was greater than in the placebo treatment group. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of "mild" or "moderate".

  Table 6. Treatment-emergent adverse reaction incidence in controlled trials in fibromyalgia (events) in at least 2% of all LYRICA-treated patients and occurring more frequently in the all pregabalin-group than in the placebo treatment group)

  System Organ Class Preferred term	150 mg/d	300 mg/d	450 mg/d	600 mg/d	All PGB *	Placebo
  	[N=132] %	[N=502] %	[N=505] %	[N=378] %	[N=1517] %	[N=505] %
  *PGB: pregabalin
  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
  Hypoesthesia	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

  Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury

  Adverse Reactions Leading to Discontinuation

  In clinical trials of patients with neuropathic pain associated with spinal cord injury, 13% of patients treated with pregabalin and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were somnolence (3%) and edema (2%). In comparison, none of the placebo-treated patients withdrew due to somnolence and edema. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue and balance disorder. Each of these adverse reactions led to withdrawal in less than 2% of patients.

  Most Common Adverse Reactions

  Table 7 lists all adverse reactions, regardless of causality, occurring in ≥2% of patients with neuropathic pain associated with spinal cord injury in the controlled trials. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of "mild" or "moderate".

  Table 7. Treatment-emergent adverse reaction incidence in controlled trials in neuropathic pain associated with spinal cord injury (events in at least 2% of all LYRICA-treated patients and occurring more frequently in the all pregabalin-group than in the placebo treatment group)

  System Organ Class Preferred term	PGB * (N=182)	Placebo (N=174)
  %	%
  *PGB: Pregabalin
  Ear and labryrinth disorders
  Vertigo	2.7	1.1
  Eye disorders
  Vision blurred	6.6	1.1
  Gastrointestinal disorders
  Dry mouth	11.0	2.9
  Constipation	8.2	5.7
  Nausea	4.9	4.0
  Vomiting	2.7	1.1
  General disorders and administration site conditions
  Fatigue	11.0	4.0
  Edema peripheral	10.4	5.2
  Edema	8.2	1.1
  Pain	3.3	1.1
  Infections and infestations
  Nasopharyngitis	8.2	4.6
  Investigations
  Weight increased	3.3	1.1
  Blood creatine phosphokinase increased	2.7	0
  Musculoskeletal and connective tissue disorders
  Muscular weakness	4.9	1.7
  Pain in extremity	3.3	2.3
  Neck pain	2.7	1.1
  Back pain	2.2	1.7
  Joint swelling	2.2	0
  Nervous system disorders
  Somnolence	35.7	11.5
  Dizziness	20.9	6.9
  Disturbance in attention	3.8	0
  Memory impairment	3.3	1.1
  Paresthesia	2.2	0.6
  Psychiatric disorders
  Insomnia	3.8	2.9
  Euphoric mood	2.2	0.6
  Renal and urinary disorders
  Urinary incontinence	2.7	1.1
  Skin and subcutaneous tissue disorders
  Decubitus ulcer	2.7	1.1
  Vascular disorders
  Hypertension	2.2	1.1
  Hypotension	2.2	0

  Other Adverse Reactions Observed During the Clinical Studies of LYRICA

  Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.

  Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section (5).

  Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock

  Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation

  Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess

  Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia

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

  Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm

  Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia, Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus

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

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

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

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

  Comparison of Gender and Race

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

  6.2 Post-marketing Experience

  The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  Nervous System Disorders – Headache

  Gastrointestinal Disorders – Nausea, Diarrhea

  Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement

  In addition, there are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when LYRICA was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are also post-marketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications.

DRUG INTERACTIONS SECTION

• 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.

USE IN SPECIFIC POPULATIONS SECTION

• 8.1 Pregnancy

  Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.

  When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established.

  When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD.

  In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥ 100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD.

  There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus.

  To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

  8.2 Labor and Delivery

  The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (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, decide 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, adjust the dose for elderly patients with renal impairment [see Dosage and Administration (2.6)].

DRUG ABUSE AND DEPENDENCE SECTION

• 9.1 Controlled Substance

  LYRICA is a Schedule V controlled substance.

  LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

  9.2 Abuse

  In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of "good drug effect," "high" and "liking" to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4 % of LYRICA-treated patients and 1 % of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%.

  9.3 Dependence

  In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions (5.8)], consistent with physical dependence. In the postmarketing experience, in addition to these reported symptoms there have also been reported cases of anxiety and hyperhidrosis

OVERDOSAGE SECTION

• 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).

SPL MEDGUIDE SECTION

• MEDICATION GUIDE

  LYRICA (LEER-i-kah)
  (pregabalin)
  Capsules and Oral Solution, CV

  Read this Medication Guide before you start taking LYRICA and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about LYRICA, ask your healthcare provider or pharmacist.

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

  LYRICA may cause serious side effects including:

  • Serious, even life-threatening, allergic reactions
  • Suicidal thoughts or actions
  • Swelling of your hands, legs and feet
  • Dizziness and sleepiness

  These serious side effects are described below:

  1.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.Swelling of your hands, legs and feet. This swelling can be a serious problem for people with heart problems.4.Dizziness and sleepiness.

  Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you. Ask your healthcare provider about when it will be okay to do these activities.

  What is LYRICA?

  LYRICA is a prescription medicine used in adults, 18 years and older, to treat:

  • pain from damaged nerves (neuropathic pain) that happens with diabetes
  • pain from damaged nerves (neuropathic pain) that follows healing of shingles
  • partial seizures when taken together with other seizure medicines
  • fibromyalgia (pain all over your body)
  • pain from damaged nerves (neuropathic pain) that follows spinal cord injury

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

  Who Should Not Take LYRICA?

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

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

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

  What should I tell my healthcare provider before taking LYRICA?

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

  • have or have had depression, mood problems or suicidal thoughts or behavior
  • have kidney problems or get kidney dialysis
  • have heart problems including heart failure
  • have a bleeding problem or a low blood platelet count
  • have abused prescription medicines, street drugs, or alcohol in the past
  • have ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema)
  • plan to father a child. Animal studies have shown that pregabalin, the active ingredient in LYRICA, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take LYRICA.
  • are pregnant or plan to become pregnant. It is not known if LYRICA will harm your unborn baby. You and your healthcare provider will have to decide if you should take LYRICA while you are pregnant. If you become pregnant while taking LYRICA, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
  • are breastfeeding. It is not known if LYRICA passes into breast milk and if it can harm your baby. You and your healthcare provider should discuss whether you should take LYRICA or breast-feed, but you should not do both

  Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins or herbal supplements. LYRICA and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take:

  • angiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have a higher chance for swelling and hives if these medicines are taken with LYRICA. See " What is the most important information I should know about LYRICA?"
  • Avandia (rosiglitazone), Avandamet (contains rosiglitazone and metformin), or Actos (pioglitazone) for diabetes. You may have a higher chance of weight gain or swelling of your hands or feet if these medicines are taken with LYRICA. See " What are the possible side effects of LYRICA."
  • any narcotic pain medicine (such as oxycodone), tranquilizers or medicines for anxiety (such as lorazepam). You may have a higher chance for dizziness and sleepiness if these medicines are taken with LYRICA.
  • any medicines that make you sleepy

  Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.

  How should I take LYRICA?

  • Take LYRICA exactly as prescribed. Your healthcare provider will tell you how much LYRICA to take and when to take it. Take LYRICA at the same times each day.
  • LYRICA may be taken with or without food.
  • Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
  • Do not stop taking LYRICA without talking to your healthcare provider. If you stop taking LYRICA suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you may feel anxious. If you have epilepsy and you stop taking LYRICA suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop LYRICA slowly.
  • If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time.
  • If you take too much LYRICA, call your healthcare provider or poison control center, or go to the nearest emergency room right away.

  What should I avoid while taking LYRICA?

  • Do not drive a car, work with machines, or do other dangerous activities until you know how LYRICA affects you.
  • Do not drink alcohol while taking LYRICA. LYRICA and alcohol can affect each other and increase side effects such as sleepiness and dizziness.

  What are the possible side effects of LYRICA?

  LYRICA may cause serious side effects, including:

  • See " What is the most important information I should know about LYRICA?"
  • muscle problems, muscle pain, soreness, or weakness. If you have these symptoms, especially if you feel sick and have a fever, tell your healthcare provider right away.
  • problems with your eyesight, including blurry vision. Call your healthcare provider if you have any changes in your eyesight.
  • weight gain. If you have diabetes, weight gain may affect the management of your diabetes. Weight gain can also be a serious problem for people with heart problems.
  • feeling "high"

  The most common side effects of LYRICA are:

  • dizziness
  • blurry vision
  • weight gain
  • sleepiness
  • trouble concentrating
  • swelling of hands and feet
  • dry mouth

  LYRICA caused skin sores in animal studies. Skin sores did not happen in studies in people. If you have diabetes, you should pay attention to your skin while taking LYRICA and tell your healthcare provider about any sores or skin problems.

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

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

  Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

  How should I store LYRICA?

  • Store LYRICA capsules and oral solution at room temperature, 59°F to 86°F (15°C to 30°C) in its original package.
  • Safely throw away any LYRICA that is out of date or no longer needed.
  • Keep LYRICA and all medicines out of the reach of children.

  General information about LYRICA

  Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LYRICA for a condition for which it was not prescribed. Do not give LYRICA to other people, even if they have the same symptoms you have. It may harm them.

  This Medication Guide summarizes the most important information about LYRICA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about LYRICA that is written for health professionals.

  You can also visit the LYRICA website at www.LYRICA.com or call 1-866-459-7422 (1-866-4LYRICA).

  What are the ingredients In LYRICA?

  Active ingredient: pregabalin

  Inactive ingredients:

  LYRICA capsules: lactose monohydrate, cornstarch, talc

  Capsule shell: gelatin and titanium dioxide; Orange capsule shell: red iron oxide; White capsule shell: sodium lauryl sulfate, colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells.

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

  LYRICA oral solution: methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water.

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

DESCRIPTION SECTION

• 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.

  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.

CLINICAL PHARMACOLOGY SECTION

• 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 has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.

  While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to 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, (2.6)].

  Pharmacokinetics in Special Populations

  Race

  In population pharmacokinetic analyses of the clinical studies in various populations, the pharmacokinetics of LYRICA were not significantly affected by race (Caucasians, Blacks, and Hispanics).

  Gender

  Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and LYRICA drug exposure is similar between genders.

  Renal Impairment and Hemodialysis

  Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, dosing must be modified [see Dosage and Administration (2.6)].

  Elderly

  Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function [see Dosage and Administration, (2.6)].

  Pediatric Pharmacokinetics

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

  Drug Interactions

  In Vitro Studies

  Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g. theophylline, caffeine) or CYP 3A4 substrates (e.g., midazolam, testosterone) is not anticipated.

  In Vivo Studies

  The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.

  Gabapentin

  The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every 8 hours and 400-mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin coadministration. The extent of pregabalin absorption was unaffected by gabapentin coadministration, although there was a small reduction in rate of absorption.

  Oral Contraceptive

  Pregabalin coadministration (200 mg three times a day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 µg, respectively) in healthy subjects.

  Lorazepam

  Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam (1 mg) had no effect on the steady-state pharmacokinetics of pregabalin.

  Oxycodone

  Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no effect on the steady-state pharmacokinetics of pregabalin.

  Ethanol

  Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0.7 g/kg) had no effect on the steady-state pharmacokinetics of pregabalin.

  Phenytoin, carbamazepine, valproic acid, and lamotrigine

  Steady-state trough plasma concentrations of phenytoin, carbamazepine and carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg three times a day) administration.

  Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant medications suggest the following:

  Therapeutic class	Specific concomitant drug studied
  Concomitant drug has no effect on the pharmacokinetics of pregabalin
  Hypoglycemics	Glyburide, insulin, metformin
  Diuretics	Furosemide
  Antiepileptic Drugs	Tiagabine
  Concomitant drug has no effect on the pharmacokinetics of pregabalin and pregabalin has no effect on the pharmacokinetics of concomitant drug
  Antiepileptic Drugs	Carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid

NONCLINICAL TOXICOLOGY SECTION

• 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.

CLINICAL STUDIES SECTION

• 14.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

  The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose. Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years. A total of 89% of patients completed Studies DPN 1 and DPN 2. The patients had a minimum mean baseline pain score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6.1 to 6.7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.

  Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three times a day with placebo. Treatment with LYRICA 100 and 200 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. There was no evidence of a greater effect on pain scores of the 200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose dependent adverse reactions [see Adverse Reactions (6.1)]. For a range of levels of improvement in pain intensity from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

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

  Study DPN 2: This 8-week study compared LYRICA 100 mg three times a day with placebo. Treatment with LYRICA 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

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

  14.2 Postherpetic Neuralgia

  The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies. These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). Seventy-three percent of patients completed the studies. The baseline mean pain scores across the 3 studies ranged from 6 to 7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.

  Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice daily with placebo. Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg, or placebo twice daily. Patients with creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily. In patients with creatinine clearance greater than 60 mL/min treatment with all doses of LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by higher rates of discontinuation due to adverse reactions. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

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

  Study PHN 2: This 8-week study compared LYRICA 100 or 200 mg three times a day with placebo, with doses assigned based on creatinine clearance. Patients with creatinine clearance between 30 to 60 mL/min were treated with 100 mg three times a day, and patients with creatinine clearance greater than 60 mL/min were treated with 200 mg three times daily. Treatment with LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 4 shows the fraction of patients achieving those levels of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

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

  Study PHN 3: This 8-week study compared LYRICA 50 or 100 mg three times a day with placebo with doses assigned regardless of creatinine clearance. Treatment with LYRICA 50 and 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by markedly higher rates of discontinuation due to adverse reactions. For various levels of improvement in pain intensity from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that level of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

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

  14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures

  The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients. Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs). Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline. During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks. The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively. Approximately half of the patients were taking 2 concurrent AEDs at baseline. Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies.

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

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

  Daily Dose of Pregabalin	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

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

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

  14.4 Management of Fibromyalgia

  The efficacy of LYRICA for management of fibromyalgia was established in one 14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2). Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). The studies showed a reduction in pain by visual analog scale. In addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the Fibromyalgia Impact Questionnaire (FIQ).

  Study F1: This 14-week study compared LYRICA total daily doses of 300 mg, 450 mg and 600 mg with placebo. Patients were enrolled with a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS). The baseline mean pain score in this trial was 6.7. Responders to placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study. A total of 64% of patients randomized to LYRICA completed the study. There was no evidence of a greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was evidence of dose-dependent adverse reactions [see Adverse Reactions (6.1)]. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study. The results are summarized in Figure 8 and Table 9.

  For various levels of improvement in pain intensity from baseline to study endpoint, Figure 8 shows the fraction of patients achieving that level of improvement. The figure is cumulative. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

  Figure 8: Patients Achieving Various Levels of Improvement in Pain Intensity – Fibromyalgia Study F1

  Table 9. Patient Global Response in Fibromyalgia Study F1

  Patient Global Impression of Change
  Treatment Group (mg/day)	% Any Improvement	95% CI
  PGB = Pregabalin
  Placebo	47.6	(40.0,55.2)
  PGB 300	68.1	(60.9, 75.3)
  PGB 450	77.8	(71.5, 84.0)
  PGB 600	66.1	(59.1, 73.1)

  Study F2: This randomized withdrawal study compared LYRICA with placebo. Patients were titrated during a 6-week open-label dose optimization phase to a total daily dose of 300 mg, 450 mg, or 600 mg. Patients were considered to be responders if they had both: 1) at least a 50% reduction in pain (VAS) and, 2) rated their overall improvement on the PGIC as "much improved" or "very much improved." Those who responded to treatment were then randomized in the double-blind treatment phase to either the dose achieved in the open-label phase or to placebo. Patients were treated for up to 6 months following randomization. Efficacy was assessed by time to loss of therapeutic response, defined as 1) less than 30% reduction in pain (VAS) from open-label baseline during two consecutive visits of the double-blind phase, or 2) worsening of FM symptoms necessitating an alternative treatment. Fifty-four percent of patients were able to titrate to an effective and tolerable dose of LYRICA during the 6-week open-label phase. Of the patients entering the randomized treatment phase assigned to remain on LYRICA, 38% of patients completed 26 weeks of treatment versus 19% of placebo-treated patients.

  When considering return of pain or withdrawal due to adverse events as loss of response (LTR), treatment with LYRICA resulted in a longer time to loss of therapeutic response than treatment with placebo. Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients remained on study drug and maintained a therapeutic response to Week 26 of the study. Treatment with LYRICA also resulted in a longer time to loss of response based on the FIQ 1, and longer time to loss of overall assessment of patient status, as measured by the PGIC 2.

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

  1Time 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. 2Time to PGIC lack of improvement was defined as time to PGIC assessments indicating less improvement than "much improvement."
  14.5 Management of Neuropathic Pain Associated with Spinal Cord Injury

  The efficacy of LYRICA for the management of neuropathic pain associated with spinal cord injury was established in two double-blind, placebo-controlled, multicenter studies. Patients were enrolled with neuropathic pain associated with spinal cord injury that persisted continuously for at least three months or with relapses and remissions for at least six months. A total of 63% of patients completed study 1 and 84% completed study 2. The patients had a minimum mean baseline pain score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6.5 to 6.7.

  Patients were allowed to take opioids, non-opioid analgesics, antiepileptic drugs, muscle relaxants, and antidepressant drugs if the dose was stable for 30 days prior to screening. Patients were allowed to take acetaminophen and nonsteroidal anti-inflammatory drugs during the studies.

  Study SCI 1: This 12-week, randomized, double-blind, parallel-group, multicenter, flexible dose (150–600 mg/day) study compared pregabalin with placebo. The 12-week study consisted of a 3-week dose adjustment phase and a 9-week dose maintenance phase. Treatment with LYRICA 150–600 mg/day statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline. The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 12 is presented in Figure 10. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

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

  Study SCI 2: This 16-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible dose (150–600 mg/day, in increments of 150 mg) study compared the efficacy, safety and tolerability of pregabalin with placebo. The 16-week study consisted of a 4-week dose adjustment phase and a 12-week dose maintenance phase. Treatment with LYRICA statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline. The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 16 is presented in Figure 11. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

  Figure 11: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 2

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