•
`
`------ DOSAGE FORMS AND STRENGTHS ------
`
`Capsules: 25mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg,
`225 mg, and 300 mg. (3)
`
`
`• Oral Solution: 20 mg/ mL. (3)
`
`
`
`
`
`------ CONTRAINDICATIONS ------
`
`• Known hypersensitivity to pregabalin or any of its
`
`components. (4)
`
`
`
`----- WARNINGS AND PRECAUTIONS ---
`
`
`
`
`• Angioedema (e.g. swelling of the throat, head and neck) can
`
`occur, and may be associated with life-threatening respiratory
`compromise requiring emergency treatment. Discontinue
`LYRICA immediately in these cases. (5.1)
`• Hypersensitivity reactions (e.g. hives, dyspnea, and
`wheezing) can occur. Discontinue LYRICA immediately in
`these patients. (5.2)
`
`
`Increased seizure frequency may occur in patients with
`
`seizure disorders if LYRICA is rapidly discontinued.
`Withdraw LYRICA gradually over a minimum of 1 week.
`(5.3)
`• Antiepileptic drugs, including LYRICA, increase the risk of
`suicidal thoughts or behavior. (5.4)
`LYRICA may cause peripheral edema. Exercise caution
`
`when co-administering LYRICA and thiazolidinedione
`antidiabetic agents. (5.5)
`• LYRICA may cause dizziness and somnolence and impair
`
`patients’ ability to drive or operate machinery.(5.6)
`
`
`
`•
`
`
`
`•
`
`
`
`------ ADVERSE REACTIONS ------
`
`Most common adverse reactions (≥ 5% and twice placebo) are
`dizziness, somnolence, dry mouth, edema, blurred vision, weight
`
`
`gain and thinking abnormal (primarily difficulty with
`
`concentration/attention). (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`Pfizer at (800) 438-1985 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------
`
`
`To enroll in the North American Antiepileptic Drug Pregnancy
`
`
`Registry call 1-888-233-2334 (toll free). (8.1 )
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved Medication Guide
`
`
`
`
`
`
`Revised: June 2011
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
` These highlights do not include all the information needed to
`
`
` use LYRICA safely and effectively. See full prescribing
` information for LYRICA.
`
`LYRICA (pregabalin) Capsules, CV
`
` LYRICA (pregabalin) Oral Solution, CV
`
` Initial U.S. Approval: 2004
`
`
`
`
`
`
` ------ INDICATIONS AND USAGE ------
`
`
`
`
`
`
`
`
`LYRICA is indicated for:
` • Neuropathic pain associated with diabetic peripheral
`
`neuropathy (DPN) (1.1)
`
`
`Post herpetic neuralgia (PHN) (1.2)
`
`•
`
`
`• Adjunctive therapy for adult patients with partial onset
`
`seizures (1.3)
`Fibromyalgia (1.4)
`
`
`
`•
`
`
`
`------ DOSAGE AND ADMINISTRATION ------
`
`
`DPN Pain (2.1):
`
`• Administer in 3 divided doses per day
`
`
`Begin dosing at 150 mg/day
`
`•
`
`• May be increased to a maximum of 300 mg/day within 1
`
`week.
`PHN (2.2):
`
`
`
`• Administer in 2 or 3 divided doses per day
`
`
`Begin dosing at 150 mg/day
`
`•
`
`• May be increased to 300 mg/day within 1 week
`
`• Maximum dose of 600 mg/day.
`Adjunctive Therapy for Adult Patients with Partial Onset
`Seizures (2.3):
`
`
`
`• Administer in 2 or 3 divided doses per day
`
`Begin dosing at 150 mg/day
`
`•
`• Maximum dose of 600 mg/day.
`Fibromyalgia (2.4):
`
`• Administer in 2 divided doses per day
`
`Begin dosing at 150 mg/day
`
`•
`
`• May be increased to 300 mg/day within 1 week
`
`• Maximum dose of 450 mg/day.
`
`
`
`
`
`Dose should be adjusted in patients with reduced renal
`function. (2.5)
`Oral Solution Concentration and Dispensing (2.6)
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2962909
`
`ARGENTUM Exhibit 1136
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`Page 00001
`
`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1 INDICATIONS AND USAGE
`
`
`
`1.1 Management of neuropathic pain associated with
`
`
`diabetic peripheral neuropathy
`
`
`
`
`1.2 Management of postherpetic neuralgia
`
`
`
`1.3 Adjunctive therapy for adult patients with partial onset
`seizures
`
`
`
`1.4 Management of Fibromyalgia
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Neuropathic pain associated with diabetic peripheral
`
`
`neuropathy
`
`
`2.2 Postherpetic neuralgia
`
`
`
`2.3 Adjunctive therapy for adult patients with partial onset
`seizures
`
`
`2.4 Fibromyalgia
`
`2.5 Patients with Renal Impairment
`
`2.6 Oral Solution Concentration and Dispensing
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Angioedema
`
`5.2 Hypersensitivity
`
`
`5.3 Withdrawal of Antiepileptic Drugs (AEDs)
`5.4 Suicidal Behavior and Ideation
`
`5.5 Peripheral Edema
`
`5.6 Dizziness and Somnolence
`
`
`5.7 Weight Gain
`
`
`5.8 Abrupt or Rapid Discontinuation
`
`
`5.9 Tumorigenic Potential
`
`
`5.10 Ophthalmological Effects
`
`
`5.11 Creatine Kinase Elevations
`
`
`5.12 Decreased Platelet Count
`
`
`5.13 PR Interval Prolongation
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trial Experience
`
`
`6.2 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Labor and Delivery
`
`
`8.3 Nursing Mothers
`
`
`* Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`
`9 DRUG ABUSE AND DEPENDENCE
`
`
`
`9.1 Controlled Substance
`
`
`9.2 Abuse
`
`
`9.3 Dependence
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`
`14.1 Neuropathic pain associated with diabetic peripheral
`
`neuropathy
`
`
`14.2 Postherpetic Neuralgia
`
`
`14.3 Adjunctive therapy for adult patients with partial
`
`onset seizures
`
`
`14.4 Fibromyalgia
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Medication Guide
`
`
`17.2 Angioedema
`
`
`17.3 Hypersensitivity
`
`17.4 Suicidal Thinking and Behavior
`
`
`17.5 Dizziness and Somnolence
`
`
`17.6 Weight Gain and Edema
`
`
`17.7 Abrupt or Rapid Discontinuation
`
`17.8 Ophthalmological Effects
`
`
`17.9 Creatine Kinase Elevations
`
`
`17.10 CNS Depressants
`
`
`17.11 Alcohol
`
`
`17.12 Use in Pregnancy
`
`
`17.13 Male Fertility
`
`
`17.14 Dermatopathy
`
`
`
`
`
`
`
`Reference ID: 2962909
`
`Page 00002
`
`

`
`FULL PRESCRIBING INFORMATION
`
`
`1 INDICATIONS AND USAGE
`
`LYRICA is indicated for:
`
`1.1 Management of neuropathic pain associated with diabetic peripheral neuropathy
`
`1.2 Management of postherpetic neuralgia
`
`1.3 Adjunctive therapy for adult patients with partial onset seizures
`
`1.4 Management of fibromyalgia
`
`2 DOSAGE AND ADMINISTRATION
`
`LYRICA is given orally with or without food.
`
`
`
`
`
`When discontinuing LYRICA, taper gradually over a minimum of 1 week.
`
`2.1 Neuropathic pain associated with diabetic peripheral neuropathy
`
`The maximum recommended dose of LYRICA is 100 mg three times a day (300 mg/day) in
`patients with creatinine clearance of at least 60 mL/min. 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 (2.5)].
`
`Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers
`additional significant benefit and this dose was less well tolerated. In view of the dose-dependent
`adverse reactions, treatment with doses above 300 mg/day is not recommended [see Adverse
`Reactions (6.1)].
`
`2.2 Postherpetic neuralgia
`
`The recommended dose of LYRICA is 75 to 150 mg two times a day, or 50 to 100 mg three
`times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min.
`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 (2.5)].
`
`Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with
`300 mg/day, and who are able to tolerate LYRICA, may be treated with up to 300 mg two times
`
`Reference ID: 2962909
`
`Page 00003
`
`

`
`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 (2.5)].
`
`The effect of dose escalation rate on the tolerability of LYRICA has not been formally studied.
`
`The efficacy of add-on LYRICA in patients taking gabapentin has not been evaluated in
`controlled trials. Consequently, dosing recommendations for the use of LYRICA with
`gabapentin cannot be offered.
`
`2.4 Management of Fibromyalgia
`
`
`
`
`
`The recommended dose of LYRICA for fibromyalgia is 300 to 450 mg/day. 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 (2.5)].
`
`
`
`2.5 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:
`
`
`Reference ID: 2962909
`
`Page 00004
`
`

`
`
`
`
`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)
` Total Pregabalin Daily Dose
`
`Dose Regimen
`
`(mL/min)
` (mg/day)*
`600
`450
`≥60
`300
`BID or TID
`150
`300
`30–60
`150
`225
`BID or TID
`75
`150
`15–30
`75
`100–150
`QD or BID
`25–50
`75
`<15
`25–50
`50–75
`QD
`25
`Supplementary dosage following hemodialysis (mg)†
`
`
`Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg
`Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg
`Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg
`Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg
`TID= Three divided doses; BID = Two divided doses; QD = Single daily dose.
`* Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.
`† Supplementary dose is a single additional dose.
`
`
`2.6 Oral Solution Concentration and Dispensing
`The oral solution is 20 mg pregabalin per milliliter (mL) and prescriptions should be written in
`milligrams (mg). The pharmacist will calculate the applicable dose in mL for dispensing (e.g.,
`150 mg equals 7.5 mL oral solution).
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg
`Oral Solution: 20 mg/mL
`[see Description (11) and How Supplied/Storage and Handling (16)].
`
`Reference ID: 2962909
`
`Page 00005
`
`

`
`4 CONTRAINDICATIONS
`
`LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its
`components. Angioedema and hypersensitivity reactions have occurred in patients receiving
`
`pregabalin therapy.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Angioedema
`
`
`
`There have been postmarketing reports of angioedema in patients during initial and chronic
`treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips,
`and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with
`respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in
`patients with these symptoms.
`
`Exercise caution when prescribing LYRICA to patients who have had a previous episode of
`angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g.,
`angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of
`developing angioedema.
`
`5.2 Hypersensitivity
`
`
`
`
`
`There have been postmarketing reports of hypersensitivity in patients shortly after initiation of
`treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea,
`and wheezing. Discontinue LYRICA immediately in patients with these symptoms.
`
`5.3 Withdrawal of Antiepileptic Drugs (AEDs)
`
`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
`
`Reference ID: 2962909
`
`Page 00006
`
`

`
`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.
`
`
`
`3.4
`8.5
`1.8
`4.3
`
`
`
`
` Table 2 Risk by indication for antiepileptic drugs in the pooled analysis
`Risk Difference:
`Relative Risk:
`Placebo Patients Drug Patients
`Indication
`
`
`Incidence of Events in Additional Drug
`with Events Per with Events Per
`
`Patients with
`1000 Patients
`1000 Patients
`Drug
`
`
`Events Per 1000
`Patients/Incidence in
`
`
`Patients
`Placebo Patients
`3.5
`2.4
`1.5
`2.9
`1.9
`0.9
`1.8
`1.9
`
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`1.0
`5.7
`1.0
`2.4
`
`
`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.
`
`
`Reference ID: 2962909
`
`Page 00007
`
`

`
`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 31% of LYRICA-treated patients
`compared to 9% of placebo-treated patients; somnolence was experienced by 22% of LYRICA-
`treated patients compared to 7% of placebo-treated patients. Dizziness and somnolence generally
`began shortly after the initiation of LYRICA therapy and occurred more frequently at higher
`doses. Dizziness and somnolence were the adverse reactions most frequently leading to
`withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these
`adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30%
`and somnolence persisted until the last dose in 42% of patients.
`
`
`Reference ID: 2962909
`
`Page 00008
`
`

`
`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, 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.
`
`
`Reference ID: 2962909
`
`Page 00009
`
`

`
`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 x 103/ µL. In randomized controlled
`trials, LYRICA was not associated with an increase in bleeding-related adverse reactions.
`
`
`Reference ID: 2962909
`
`Page 00010
`
`

`
`5.13 PR Interval Prolongation
`
`LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial
`ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This
`
` mean change difference was not associated with an increased risk of PR increase ≥25% from
`baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased
`risk of adverse reactions of second or third degree AV block.
`
`Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline
`PR prolongation or in patients taking other PR prolonging medications. However, these analyses
`cannot be considered definitive because of the limited number of patients in these categories.
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`of another drug and may not reflect the rates observed in practice.
`
`In all controlled and uncontrolled trials across various patient populations during the
`premarketing development of LYRICA, more than 10,000 patients have received LYRICA.
`Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated
`for 1 year or longer, and over 1400 patients were treated for at least 2 years.
`
`Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled
`Clinical Studies
`
`
`
`
`
`In premarketing controlled trials of all populations combined, 14% of patients treated with
`LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse
`reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to
`discontinuation were dizziness (4%) and somnolence (3%). In the placebo group, 1% of patients
`withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that
`led to discontinuation from controlled trials more frequently in the LYRICA group compared to
`the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision,
`incoordination, and peripheral edema (1% each).
`
`
`
`Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies
`
`In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry
`mouth, edema, blurred vision, weight gain, and "thinking abnormal" (primarily difficulty with
`concentration/attention) were more commonly reported by subjects treated with LYRICA than
`by subjects treated with placebo (≥5% and twice the rate of that seen in placebo).
`
`
`Reference ID: 2962909
`
`Page 00011
`
`

`
`
`
` 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
`
`150
`75
`mg/day
`mg/day
`[N=212]
`[N=77]
`%
`%
`Body as a whole
`
`
`
`2
`4
`Asthenia
`
`2
`5
`Accidental injury
`2
`0
`Back pain
`1
`4
`Chest pain
`
`1
`0
`Face edema
`
`
`
`Digestive system
`
`
`
`2
`3
`Dry mouth
`2
`0
`Constipation
`0
`3
`Flatulence
`
`
`
`Metabolic and nutritional disorders
`
`6
`Peripheral edema
`4
`Weight gain
`0
`4
`Edema
`0
`2
`Hypoglycemia
`1
`3
`
`
`
`Nervous system
`
`
`
`
`300
`mg/day
`[N=321]
`%
`
`4
`2
`1
`1
`1
`
`
`5
`4
`2
`
`
`600
`mg/day
`[N=369]
`%
`
`7
`6
`2
`2
`2
`
`
`7
`6
`3
`
`
`All PGB*
`[N=979]
`%
`
`5
`4
`2
`2
`1
`
`
`5
`4
`2
`
`
`
`
`
`
`9
`4
`4
`2
`
`
`
`12
`6
`2
`1
`
`
`
`9
`4
`2
`2
`
`
`
`Placebo
`[N=459]
`%
`
`2
`3
`0
`1
`0
`
`
`1
`2
`1
`
`2
`0
`0
`1
`
`
`
`Reference ID: 2962909
`
`Page 00012
`
`

`
`8
`4
`9
`6
`1
`0
`0
`1
`1
`1
`1
`3
`0
`
`
`3
`
`
`3
`1
`
`9
`6
`2
`1
`2
`1
`0
`0
`0
`1
`0
`1
`1
`
`
`0
`
`
`1
`0
`
`23
`13
`2
`2
`2
`2
`3
`2
`1
`1
`1
`0
`1
`
`
`2
`
`
`3
`1
`
`29
`16
`5
`4
`4
`3
`2
`2
`3
`2
`3
`2
`1
`
`
`2
`
`
`6
`1
`
`21
`12
`4
`3
`3
`2
`2
`2
`