2.1 Important Dosage and Administration Instructions

LYRICA CR should be administered once daily after an evening meal.

LYRICA CR should be swallowed whole and should not be split, crushed, or chewed.

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

Instruct patients that if they miss taking their dose of LYRICA CR after an evening meal, then they should take their usual dose of LYRICA CR prior to bedtime following a snack. If they miss taking the dose of LYRICA CR prior to bedtime, then they should take their usual dose of LYRICA CR following a morning meal. If they miss taking the dose of LYRICA CR following the morning meal, then they should take their usual dose of LYRICA CR at the usual time that evening following an evening meal [see Patient Counseling Information (17)].

2.2 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

Begin dosing at 165 mg once daily and increase to 330 mg once daily within 1 week based on individual patient response and tolerability. The maximum recommended dose of LYRICA CR is 330 mg once daily.

Although LYRICA was studied at 600 mg/day, there was no evidence that this dose conferred additional significant benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions with LYRICA, treatment with doses above 330 mg/day is not recommended for LYRICA CR.

2.3 Postherpetic Neuralgia

Begin dosing at 165 mg once daily and increase to 330 mg once daily within 1 week based on individual patient response and tolerability.

Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 330 mg once daily and who are able to tolerate LYRICA CR, may be treated with up to 660 mg once daily. In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, dosing above 330 mg/day should be reserved only for those patients who have on-going pain and are tolerating 330 mg daily. The maximum recommended dose of LYRICA CR is 660 mg once daily.

2.4 Conversion from LYRICA Capsules or Oral Solution to LYRICA CR

When switching from LYRICA to LYRICA CR on the day of the switch, instruct patients to take their morning dose of LYRICA as prescribed and initiate LYRICA CR therapy after an evening meal.

2.5 Patients with Renal Impairment

Use of LYRICA CR is not recommended for patients with creatinine clearance (CLcr) less than 30 mL/min or who are undergoing hemodialysis. Those patients should receive LYRICA.

In view of dose-dependent adverse reactions and because pregabalin 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 CLcr, as indicated in Table 2. To use the dosing tables, 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 greater than or equal to 60 mL/min). Then refer to Table 2 to determine the corresponding renal adjusted dose.

(For example: A patient initiating LYRICA CR therapy for postherpetic neuralgia with normal renal function [CLcr greater than or equal to 60 mL/min], receives a single daily dose of 165 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a single daily dose of 82.5 mg.)

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 CR immediately in patients with these symptoms.

Exercise caution when prescribing LYRICA CR 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 Reactions

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

5.3 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including pregabalin, the active ingredient in LYRICA CR, 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 3 shows absolute and relative risk by indication for all evaluated AEDs.

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 CR must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. 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 CR can 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.

5.4 Respiratory Depression

There is evidence from case reports, human studies, and animal studies associating pregabalin with serious, life-threatening, or fatal respiratory depression when co-administered with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe LYRICA CR with another CNS depressant, particularly an opioid, or to prescribe LYRICA CR to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating LYRICA CR at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including LYRICA CR).

There is more limited evidence from case reports, animal studies, and human studies associating pregabalin with serious respiratory depression, without co-administered CNS depressants or without underlying respiratory impairment.

5.5 Dizziness and Somnolence

LYRICA CR may cause dizziness and somnolence. Inform patients that LYRICA CR-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. Concomitant use of LYRICA CR with other central nervous system (CNS) depressants may exacerbate these effects [see Drug Interactions (7)].

In the LYRICA CR controlled trials for pain indications, dizziness was experienced by 24% of LYRICA CR-treated patients during the single-blind phase; somnolence was experienced by 15.8% of LYRICA CR-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA CR therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (2.4%, 1.2% each) during the single-blind phase of the controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients.

5.6 Risks Associated with Abrupt or Rapid Discontinuation

Following abrupt or rapid discontinuation of LYRICA CR, some patients reported symptoms including, insomnia, nausea, headache, anxiety, and diarrhea. Increased seizure frequency may occur in patients with seizure disorders taking LYRICA CR for pain if LYRICA CR is rapidly discontinued. Taper LYRICA CR gradually over a minimum of 1 week rather than discontinuing the drug abruptly. The efficacy of LYRICA CR as adjunctive therapy for adult patients with partial onset seizures has not been established.

5.7 Peripheral Edema

LYRICA CR 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 for pain indications, the incidence of peripheral edema for patients receiving LYRICA CR in the single-blind phase was 5.3% of patients. In controlled clinical trials for pain indications, 0.8% of LYRICA CR patients withdrew due to peripheral edema during the single-blind phase.

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, monitor patients for the development of edema when co-administering LYRICA CR 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, monitor these patients for possible exacerbation of congestive heart failure symptoms when using LYRICA CR.

5.8 Weight Gain

LYRICA CR treatment may cause weight gain. In LYRICA CR controlled trials for pain indications, weight gain was experienced by 4% of LYRICA CR-treated patients during the single-blind phase. Adverse events of weight gain were observed in 3.7% of LYRICA CR-treated patients and 1% of placebo-treated patients during the double-blind phase.

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. In studies with LYRICA, associated weight gain was related to pregabalin 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 (5.7)].

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

5.9 Tumorigenic Potential

In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, an unexpectedly high incidence of hemangiosarcoma was identified in 2 different strains of mice [see Nonclinical Toxicology (13.1)]. The clinical significance of this finding is unknown. Clinical experience during premarketing development of LYRICA 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 greater than 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 pregabalin, 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 for pain indications, 4.8% of patients treated with LYRICA CR in the single-blind phase reported blurred vision, which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA CR treatment due to vision-related events (primarily blurred vision). Additionally, 0.7% of LYRICA CR-treated patients as compared to no placebo-treated patients experienced blurred vision in the double-blind phase.

Prospectively planned ophthalmologic testing during the premarketing development of pregabalin, 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 LYRICA-treated patients 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.

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 3 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 CR if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.

5.12 Decreased Platelet Count

Both LYRICA CR and LYRICA treatment were associated with a decrease in platelet count. In the double-blind phase of controlled studies for pain indication, LYRICA CR-treated patients experienced a median change from baseline in platelet count of 11 × 103/mm3 (for the PHN population) and 14 × 103/mm3 (for the FM population) as compared to 1 × 103/mm3 in placebo-treated patients (for both populations). LYRICA-treated patients 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 less than 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 or LYRICA CR were 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 pregabalin doses greater than or equal to 300 mg/day. This mean change difference was not associated with an increased risk of PR increase greater than or equal to 25% from baseline, an increased percentage of subjects with on-treatment PR greater than 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.

6.1 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.

Two randomized placebo-controlled clinical trials were conducted in patients with postherpetic neuralgia and fibromyalgia in which a total of 1242 patients received LYRICA CR. Both studies were randomized withdrawal design where a 6-week single-blind, dose optimization phase was followed by a 13-week double-blind phase. The most common adverse events leading to discontinuation from the single-blind phase of the study occurring in greater than or equal to 0.3% of patients were dizziness, somnolence, peripheral edema, fatigue, blurred vision, and increased weight. Sixty-four percent of patients experienced adverse events during the single-blind phase, with the most common adverse events occurring in greater than or equal to 4% of patients being dizziness, somnolence, headache, fatigue, peripheral edema, nausea, blurred vision, dry mouth, and weight gain.

6.2 Postmarketing Experience with LYRICA

The following adverse reactions have been identified during post-approval use of LYRICA. These adverse reactions have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: breast enlargement, bullous pemphigoid, gynecomastia.

There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking pregabalin with opioids or other CNS depressants, or in the setting of underlying respiratory impairment.

In addition, there are postmarketing 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.

Pharmacodynamics

Although no pharmacokinetic interactions were seen with LYRICA and ethanol, lorazepam, or oxycodone, 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 in studies of LYRICA.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of LYRICA CR in pediatric patients have not been 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 the LYRICA CR neuropathic pain associated with postherpetic neuralgia study, 422 patients 65 years of age and older received pregabalin.

No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pregabalin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. See Dosage and Administration (2.5) for recommendations for dosing in patients with renal impairment.

9.1 Controlled Substance

LYRICA CR contains pregabalin, a Schedule V controlled substance.

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%.

Carefully evaluate all patients treated with LYRICA CR for history of drug abuse and observe them for signs of LYRICA CR misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

9.3 Dependence

In clinical studies, following abrupt or rapid discontinuation of LYRICA CR, some patients reported symptoms including insomnia, nausea, headache diarrhea, or anxiety [see Warnings and Precautions (5.6)], consistent with physical dependence. In the postmarketing experience with LYRICA, in addition to these reported symptoms there have also been reported cases of hyperhidrosis.

Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans

In the postmarketing experience, the most commonly reported adverse events observed with pregabalin when taken in overdose include reduced consciousness, depression/anxiety, confusional state, agitation, and restlessness. Seizures and heart block have also been reported. Deaths have been reported in the setting of lone LYRICA overdose and in combination with other CNS depressants.

Treatment or Management of Overdose

There is no specific antidote for overdose with pregabalin. 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 pregabalin.

Pregabalin can be removed by hemodialysis. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).

12.1 Mechanism of Action

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

LYRICA CR has linear pharmacokinetics with dose-proportional increases in maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from 82.5–660 mg/day. Following repeated administration, steady state is achieved within approximately 48–72 hours.

LYRICA CR administered once daily following an evening meal has equivalent AUC and lower Cmax relative to a comparative dose of LYRICA administered without food twice daily (Table 5). Variability in Cmax and AUC for LYRICA CR is less than or equal to 25%.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14.1 Management of Postherpetic Neuralgia (Study PHN CR)

Support for efficacy of LYRICA CR for the management of PHN and diabetic peripheral neuropathy (DPN) was based on the efficacy of LYRICA for these indications along with an adequate and well-controlled study in adults with PHN. This 19-week randomized withdrawal study compared daily doses of LYRICA CR 82.5 mg, 165 mg, 247.5 mg, 330 mg, 495 mg, or 660 mg with placebo. Those enrolled were required to have pain present for more than 3 months after healing of the herpes zoster skin rash and a baseline pain score of greater than or equal to 4 on the numeric rating scale (NRS)-Pain (assessed over a 1 week recall period). The baseline mean pain scores were 6.83 for LYRICA CR-treated patients vs. 6.85 for placebo-treated patients. A total of 82.4% of patients completed the single-blind phase of the study. Patients were considered responders if they had at least a 50% reduction in pain in the single-blind phase. Those who responded to treatment were then randomized in the double-blind phase to treatment with either the LYRICA CR dose achieved in the single-blind phase or placebo. Patients were treated for up to 3 months following randomization. A total of 87.5% of LYRICA CR-treated patients and 78% of placebo-treated patients completed the double-blind phase of the study.

LYRICA CR treatment demonstrated statistically significant improvement in the endpoint change in mean pain score from baseline compared to placebo. For a range of levels of improvement in pain intensity from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. In the LYRICA CR group, 79.8% of subjects achieved at least a 30% improvement and 73.6% at least 50% improvement in pain intensity. In the placebo group, 64.9% of subjects achieved at least a 30% improvement and 54.6% at least a 50% improvement in pain intensity.

Figure 1. Percent of Patients Achieving Various Levels of Improvement in Pain Intensity (N=413)

14.2 Management of Fibromyalgia (Study FM CR)

A double-blind, placebo-controlled, randomized withdrawal trial of LYRICA CR in adults with fibromyalgia failed to demonstrate efficacy.

14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures

A double-blind, placebo-controlled, randomized trial of LYRICA CR as adjunctive therapy in adults with partial onset seizures failed to demonstrate efficacy.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F) in the original package. (See USP Controlled Room Temperature)

Angioedema

Advise patients that LYRICA CR may cause angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue LYRICA CR and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.1)].

Hypersensitivity

Advise patients that LYRICA CR has been associated with hypersensitivity reactions such as skin redness, blisters, hives, rash, dyspnea, and wheezing. Instruct patients to discontinue LYRICA CR and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.2)].

Suicidal Thinking and Behavior

Counsel patients, their caregivers, and families that AEDs, including pregabalin, the active ingredient in LYRICA CR, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to a healthcare provider [see Warnings and Precautions (5.3)].

Respiratory Depression

Inform patients about the risk of respiratory depression. Include information that the risk is greatest for those using concomitant central nervous system (CNS) depressants (such as opioid analgesics) or in those with underlying respiratory impairment. Teach patients how to recognize respiratory depression and advise them to seek medical attention immediately if it occurs [see Warnings and Precautions (5.4)].

Dizziness and Somnolence

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

CNS Depressants

Inform patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines that they may experience additive CNS side effects, such as respiratory depression, somnolence, and dizziness [see Warnings and Precautions (5.4, 5.5) and Drug Interactions (7)]. Advise patients to avoid consuming alcohol while taking LYRICA CR, as LYRICA CR may potentiate the impairment of motor skills and sedating effects of alcohol [see Drug Interactions (7)].

Abrupt or Rapid Discontinuation

Advise patients to take LYRICA CR as prescribed. Abrupt or rapid discontinuation may result in insomnia, nausea, headache, anxiety, or diarrhea. Advise patients with seizure disorders that abrupt or rapid discontinuation may increase seizure frequency [see Warnings and Precautions (5.6)].

Missed Dose

Instruct patients that if they miss taking their dose of LYRICA CR after an evening meal, then they should take their usual dose of LYRICA CR prior to bedtime following a snack. If they miss taking the dose of LYRICA CR prior to bedtime, then they should take their usual dose of LYRICA CR following a morning meal. If they miss taking the dose of LYRICA CR following the morning meal, then they should take their usual dose of LYRICA CR at the usual time that evening following an evening meal.

Weight Gain and Edema

Inform patients that LYRICA CR may cause edema and weight gain. Advise patients that concomitant treatment with LYRICA CR and a thiazolidinedione antidiabetic agent may lead to an additive effect on edema and weight gain. Advise patients with preexisting cardiac conditions that this may increase the risk of heart failure [see Warnings and Precautions (5.7, 5.8)].

Ophthalmological Effects

Counsel patients that LYRICA CR may cause visual disturbances. Inform patients that if changes in vision occur, they should notify their physician [see Warnings and Precautions (5.10)].

Creatine Kinase Elevations

Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever [see Warnings and Precautions (5.11)].

Use in Pregnancy

Advise pregnant patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry [see Use in Specific Populations (8.1)].

Lactation

Advise nursing mothers that breastfeeding is not recommended during treatment with LYRICA CR [see Use in Specific Populations (8.2)].

Male Fertility

Inform men being treated with LYRICA CR who plan to father a child of the potential risk of male-mediated teratogenicity [see Nonclinical Toxicology (13.1) and Use in Specific Populations (8.3)].

Dermatopathy

Instruct diabetic patients to pay particular attention to skin integrity while being treated with LYRICA CR [see Nonclinical Toxicology (13.2)].