2.1 Important Administration Instructions

Pregabalin capsules are given orally with or without food.

 When discontinuing pregabalin capsules, taper gradually over a minimum of 1 week [see Warnings and Precautions (5.3)].

Because pregabalin is eliminated primarily by renal excretion, adjust the dose in adult patients with reduced renal function [see Dosage and Administration (2.7)].

2.2 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy in Adults

The maximum recommended dose of pregabalin capsules 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.

Although pregabalin 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)].

2.3 Postherpetic Neuralgia in Adults

The recommended dose of pregabalin capsules 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.

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 pregabalin, 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)].

2.4 Adjunctive Therapy for Partial-Onset Seizures in Patients 17 Years of Age and Older

The recommended dosage for adult patients 17 years of age and older is included in Table 1. Administer the total daily dosage orally in two or three divided doses as indicated in Table 1. Based on clinical response and tolerability, dosage may be increased, approximately weekly.

Table 1. Recommended Dosage for Adult Patients 17 Years and Older

Both the efficacy and adverse event profiles of pregabalin have been shown to be dose-related.

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

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

Pediatric use information is approved for Pfizer's LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.5 Management of Fibromyalgia in Adults

The recommended dose of pregabalin capsules 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 pregabalin 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)].

2.6 Neuropathic Pain Associated with Spinal Cord Injury in Adults

The recommended dose range of pregabalin capsules 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 pregabalin may be treated with up to 300 mg two times a day [see Clinical Studies (14.5)].

2.7 Dosing for Adult Patients with Renal Impairment

In view of dose-dependent adverse reactions and since pregabalin is eliminated primarily by renal excretion, adjust the dose in adult patients with reduced renal function. The use of pregabalin capsules in pediatric patients with compromised renal function has not been studied.

Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 2. 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 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 pregabalin therapy for postherpetic neuralgia with normal renal function (CLcr greater than or equal to 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 2).

Table 2. Pregabalin Dosage Adjustment Based on Renal Function

 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.

5.1 Angioedema

There have been postmarketing reports of angioedema in patients during initial and chronic treatment with pregabalin. 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 pregabalin immediately in patients with these symptoms.

Exercise caution when prescribing pregabalin 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 pregabalin. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin immediately in patients with these symptoms.

5.3 Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation

As with all antiepileptic drugs (AEDs), withdraw pregabalin gradually to minimize the potential of increased seizure frequency in patients with seizure disorders.

Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea.

If pregabalin is discontinued, taper the drug gradually over a minimum of 1 week rather than discontinue the drug abruptly.

5.4 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including pregabalin, 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 to 100 years) in the clinical trials analyzed.

Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

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 pregabalin 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.

5.5 Peripheral Edema

Pregabalin 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 in adult patients, the incidence of peripheral edema was 6% in the pregabalin group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of pregabalin 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 pregabalin 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 pregabalin only, and 19% (23/120) of patients who were on both pregabalin and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on pregabalin 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 pregabalin 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 pregabalin in these patients.

5.6 Dizziness and Somnolence

Pregabalin may cause dizziness and somnolence. Inform patients that pregabalin-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery [see Patient Counseling Information (17)].

In the pregabalin controlled trials in adult patients, dizziness was experienced by 30% of pregabalin-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of pregabalin-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of pregabalin 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 pregabalin-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)].

Pediatric use information is approved for Pfizer's LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

5.7 Weight Gain

Pregabalin treatment may cause weight gain. In pregabalin controlled clinical trials in adult patients of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of pregabalin-treated patients and 2% of placebo-treated patients. Few patients treated with pregabalin (0.3%) withdrew from controlled trials due to weight gain. Pregabalin 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 pregabalin-associated weight gain are unknown.

Among diabetic patients, pregabalin-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 pregabalin 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, pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C).

5.8 Tumorigenic Potential

In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, 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 pregabalin's premarketing development provides no direct means to assess its potential for inducing tumors in humans.

In clinical studies across various patient populations, comprising 6,396 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.

5.9 Ophthalmological Effects

In controlled studies in adult patients, a higher proportion of patients treated with pregabalin 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 pregabalin 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 3,600 patients. In these patients, visual acuity was reduced in 7% of patients treated with pregabalin, and 5% of placebo-treated patients. Visual field changes were detected in 13% of pregabalin-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of pregabalin-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)].

5.10 Creatine Kinase Elevations

Pregabalin treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for pregabalin-treated patients and 28 U/L for the placebo patients. In all controlled trials in adult patients across multiple patient populations, 1.5% of patients on pregabalin and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three pregabalin-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and pregabalin 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 pregabalin if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.

5.11 Decreased Platelet Count

Pregabalin treatment was associated with a decrease in platelet count. Pregabalin-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 in adult patients, 2% of placebo patients and 3% of pregabalin patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and less than 150 × 103/µL. A single pregabalin-treated subject developed severe thrombocytopenia with a platelet count less than 20 × 103/ µL. In randomized controlled trials, pregabalin was not associated with an increase in bleeding-related adverse reactions.

5.12 PR Interval Prolongation

Pregabalin treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data in adult patients, the mean PR interval increase was 3 to 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.

In all controlled and uncontrolled trials across various patient populations during the premarketing development of pregabalin, more than 10,000 patients have received pregabalin. Approximately 5,000 patients were treated for 6 months or more, over 3,100 patients were treated for 1 year or longer, and over 1,400 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 adult populations combined, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin 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 less than 1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the pregabalin 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 Controlled Clinical Studies in Adults
In premarketing controlled trials of all adult patient populations combined (including DPN, PHN, and adult patients with partial-onset seizures), 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 pregabalin than by subjects treated with placebo (greater than or equal to 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 adults with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with pregabalin and 4% 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 (3%) and somnolence (2%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin 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 4 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with diabetic neuropathy in the combined pregabalin group for which the incidence was greater in this combined pregabalin 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 4. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

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

Controlled Studies in Postherpetic Neuralgia

Adverse Reactions Leading to Discontinuation

In clinical trials in adults with postherpetic neuralgia, 14% of patients treated with pregabalin and 7% 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 (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 pregabalin 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 5 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. In addition, an event is included, even if the incidence in the all pregabalin 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 5. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia

* PGB: pregabalin

† Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking.

‡ Investigator term; summary level term is amblyopia

Controlled Studies of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients

Adverse Reactions Leading to Discontinuation
Approximately 15% of patients receiving pregabalin and 6% of patients receiving placebo in trials of adjunctive therapy for partial-onset seizures discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, less than 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 pregabalin 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 6 lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-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 pregabalin and 294 patients received placebo for up to 12 weeks. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of "mild" or "moderate".

Table 6. Dose-related Adverse Reaction Incidence in Controlled Trials of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients

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

Controlled Studies with Fibromyalgia

Adverse Reactions Leading to Discontinuation
In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150 to 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, less than 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 9 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 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 9. Adverse Reaction Incidence in Controlled Trials in Fibromyalgia

* PGB: pregabalin

Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury

Adverse Reactions Leading to Discontinuation

In clinical trials of adults 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 10 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients for which the incidence was greater than in the placebo treatment group 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 10. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Spinal Cord Injury

* PGB: Pregabalin

Other Adverse Reactions Observed During the Clinical Studies of Pregabalin

Following is a list of treatment-emergent adverse reactions reported by patients treated with pregabalin 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 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, Alanine aminotransferase increased, Aspartate aminotransferase increased

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.

Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of pregabalin. 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 postmarketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are also postmarketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications.

Pharmacodynamics

Multiple oral doses of pregabalin 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 pregabalin was co-administered with these drugs. No clinically important effects on respiration were seen.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Neuropathic Pain Associated with Diabetic Peripheral Neuropathy, Postherpetic Neuralgia, and Neuropathic Pain Associated with Spinal Cord Injury

Safety and effectiveness in pediatric patients have not been established.

Fibromyalgia

Safety and effectiveness in pediatric patients have not been established.

Adjunctive Therapy for Partial-Onset Seizures

Safety and effectiveness in pediatric patients below the age of 1 month have not been established.

8.5 Geriatric Use

In controlled clinical studies of pregabalin 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 pregabalin 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 pregabalin 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 pregabalin 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.

Pregabalin is known to be substantially excreted by the kidney, and the risk of toxic reactions to pregabalin may be greater in patients with impaired renal function. Because pregabalin is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see Dosage and Administration (2.7)].

8.6 Renal Impairment

Pregabalin is eliminated primarily by renal excretion and dose adjustment is recommended for adult patients with renal impairment [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)]. The use of pregabalin in pediatric patients with compromised renal function has not been studied.

9.1 Controlled Substance

Pregabalin is a Schedule V controlled substance.

Pregabalin 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 pregabalin 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, pregabalin (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 5,500 patients, 4% of pregabalin-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 pregabalin, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions (5.3)], consistent with physical dependence. In the postmarketing experience, in addition to these reported symptoms there have also been reported cases of anxiety and hyperhidrosis.

Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans

There is limited experience with overdose of pregabalin. The highest reported accidental overdose of pregabalin during the clinical development program was 8,000 mg, and there were no notable clinical consequences.

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.

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).

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

Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an elimination half-life of about 6 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

The efficacy of the maximum recommended dose of pregabalin 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 greater than or equal to 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.

14.2 Postherpetic Neuralgia

The efficacy of pregabalin 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 greater than or equal to 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.

14.3 Adjunctive Therapy for Partial-Onset Seizures in Patients 17 Years of Age and Older

Adjunctive Therapy for Partial-Onset Seizures in Adult Patients
The efficacy of pregabalin as adjunctive therapy for partial-onset seizures in adult patients was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies. 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 pregabalin-treated patients, 80% completed the double-blind phase of the studies.

Table 11 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.

In the first study (E1), there was evidence of a dose-response relationship for total daily doses of pregabalin 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 greater than or equal to 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 Adjunctive 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 pregabalin showed no clinically important differences as a function of age, gender, or race.

Pediatric use information is approved for Pfizer's LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

14.4 Management of Fibromyalgia

The efficacy of pregabalin 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).

14.5 Management of Neuropathic Pain Associated with Spinal Cord Injury

The efficacy of pregabalin 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 greater than or equal to 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.

Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]

Dispense in tight container.